Methods Of Treating A Metabolic Disorder With Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) Inhibitors

ABSTRACT

The present disclosure provides methods of treating a subject having a metabolic disorder or is at risk of developing a metabolic disorder or preventing a subject from developing a metabolic disorder, and methods of identifying subjects having an increased risk of developing a metabolic disorder.

REFERENCE TO SEQUENCE LISTING

This application includes a Sequence Listing filed electronically as atext file named 18923807801SEQ, created on Jun. 25, 2022, with a size of297 kilobytes. The Sequence Listing is incorporated herein by reference.

FIELD

The present disclosure relates generally to the treatment of subjectshaving a metabolic disorder or at risk of developing a metabolicdisorder with Mitogen-Activated Protein Kinase Kinase Kinase 15(MAP3K15) inhibitors, and methods of identifying subjects having anincreased risk of developing a metabolic disorder.

BACKGROUND

The global epidemic of Type-2 diabetes is a major public health problem,as this disease is the fifth leading cause of death worldwide and aleading cause of morbidity, premature coronary heart disease, stroke,peripheral vascular disease, renal failure, and amputation. The numberof individuals living with diabetes worldwide is predicted to increasefrom 366 million in 2011 to 552 million by 2030. Type-2 diabetes is anon-insulin-dependent diabetes that is characterized by hyperglycemiadue to impaired insulin secretion and insulin resistance in targettissues. Type-2 diabetes is typically diagnosed after the age of 40years and is caused by the combined action of genetic susceptibility andenvironmental factors. Type-2 diabetes is associated with obesity, andit is also a polygenic disease.

Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) encodes aubiquitously expressed, mitogen-activated protein kinase involved inapoptotic cell-death (Kaji et al., Biochem. Biophys. Res. Commun., 2010,395, 213-218), not previously implicated in type-2 diabetes.

SUMMARY

The present disclosure provides methods of treating a subject having ametabolic disorder or at risk of developing a metabolic disorder, themethods comprising administering a MAP3K15 inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving Type-2 diabetes or at risk of developing Type-2 diabetes, themethods comprising administering a MAP3K15 inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving increased hemoglobin A1c or at risk of developing increasedhemoglobin A1c, the methods comprising administering a MAP3K15 inhibitorto the subject.

The present disclosure also provides methods of treating a subjecthaving increased serum glucose or at risk of developing increased serumglucose, the methods comprising administering a MAP3K15 inhibitor to thesubject.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or prevents a metabolic disorder,wherein the subject has a metabolic disorder or is at risk of developinga metabolic disorder, the methods comprising the steps of: determiningwhether the subject has a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide by: obtainingor having obtained a biological sample from the subject; and performingor having performed a sequence analysis on the biological sample todetermine if the subject has a genotype comprising the MAP3K15 missensevariant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide; and: i) administering or continuing toadminister the therapeutic agent that treats or prevents the metabolicdisorder in a standard dosage amount to a subject that is MAP3K15reference, and/or administering a MAP3K15 inhibitor to the subject; ii)administering or continuing to administer the therapeutic agent thattreats or prevents the metabolic disorder in an amount that is the sameas or less than a standard dosage amount to a subject that isheterozygous for the MAP3K15 missense variant nucleic acid molecule,and/or administering a MAP3K15 inhibitor to the subject; or iii)administering or continuing to administer the therapeutic agent thattreats or prevents the metabolic disorder in an amount that is the sameas or less than a standard dosage amount to a subject that is homozygousfor the MAP3K15 missense variant nucleic acid molecule; wherein thepresence of a genotype having the MAP3K15 missense variant nucleic acidmolecule encoding the MAP3K15 predicted loss-of-function polypeptideindicates the subject has a decreased risk of developing the metabolicdisorder.

The present disclosure also provides methods of identifying a subjecthaving an increased risk of developing a metabolic disorder, the methodscomprising: determining or having determined the presence or absence ofa MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide in a biological sample obtainedfrom the subject; when the subject is MAP3K15 reference, then thesubject has an increased risk of developing the metabolic disorder; andwhen the subject is heterozygous or homozygous for the MAP3K15 missensevariant nucleic acid molecule encoding the MAP3K15 predictedloss-of-function polypeptide, then the subject has a decreased risk ofdeveloping the metabolic disorder.

The present disclosure also provides therapeutic agents that treat orprevent a metabolic disorder for use in the treatment or prevention ofthe metabolic disorder in a subject having: a MAP3K15 missense variantgenomic nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide; a MAP3K15 missense variant mRNA moleculeencoding a MAP3K15 predicted loss-of-function polypeptide; or a MAP3K15missense variant cDNA molecule encoding a MAP3K15 predictedloss-of-function polypeptide.

The present disclosure also provides MAP3K15 inhibitors for use in thetreatment or prevention of a metabolic disorder in a subject that: a) isreference for a MAP3K15 genomic nucleic acid molecule, a MAP3K15 mRNAmolecule, or a MAP3K15 cDNA molecule; or b) is heterozygous for: i) aMAP3K15 missense variant genomic nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide; ii) a MAP3K15 missensevariant mRNA molecule encoding a MAP3K15 predicted loss-of-functionpolypeptide; or iii) a MAP3K15 missense variant cDNA molecule encoding aMAP3K15 predicted loss-of-function polypeptide.

DESCRIPTION

Various terms relating to aspects of the present disclosure are usedthroughout the specification and claims. Such terms are to be giventheir ordinary meaning in the art, unless otherwise indicated. Otherspecifically defined terms are to be construed in a manner consistentwith the definitions provided herein.

Unless otherwise expressly stated, it is in no way intended that anymethod or aspect set forth herein be construed as requiring that itssteps be performed in a specific order. Accordingly, where a methodclaim does not specifically state in the claims or descriptions that thesteps are to be limited to a specific order, it is in no way intendedthat an order be inferred, in any respect. This holds for any possiblenon-expressed basis for interpretation, including matters of logic withrespect to arrangement of steps or operational flow, plain meaningderived from grammatical organization or punctuation, or the number ortype of aspects described in the specification.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means that the recited numerical valueis approximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical value is used,unless indicated otherwise by the context, the term “about” means thenumerical value can vary by ±10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “comprising” may be replaced with “consisting”or “consisting essentially of” in particular embodiments as desired.

As used herein, the term “isolated”, in regard to a nucleic acidmolecule or a polypeptide, means that the nucleic acid molecule orpolypeptide is in a condition other than its native environment, such asapart from blood and/or animal tissue. In some embodiments, an isolatednucleic acid molecule or polypeptide is substantially free of othernucleic acid molecules or other polypeptides, particularly other nucleicacid molecules or polypeptides of animal origin. In some embodiments,the nucleic acid molecule or polypeptide can be in a highly purifiedform, i.e., greater than 95% pure or greater than 99% pure. When used inthis context, the term “isolated” does not exclude the presence of thesame nucleic acid molecule or polypeptide in alternative physical forms,such as dimers or Alternately phosphorylated or derivatized forms.

As used herein, the terms “nucleic acid”, “nucleic acid molecule”,“nucleic acid sequence”, “polynucleotide”, or “oligonucleotide” cancomprise a polymeric form of nucleotides of any length, can comprise DNAand/or RNA, and can be single-stranded, double-stranded, or multiplestranded. One strand of a nucleic acid also refers to its complement.

As used herein, the term “subject” includes any animal, includingmammals. Mammals include, but are not limited to, farm animals (such as,for example, horse, cow, pig), companion animals (such as, for example,dog, cat), laboratory animals (such as, for example, mouse, rat,rabbits), and non-human primates. In some embodiments, the subject is ahuman. In some embodiments, the human is a patient under the care of aphysician.

It has been observed in accordance with the present disclosure thatMAP3K15 missense variant nucleic acid molecules encoding MAP3K15predicted loss-of-function polypeptides (whether these variations arehomozygous or heterozygous in a particular subject) associate with adecreased risk of developing a metabolic disorder. It is believed thatthe MAP3K15 missense variant nucleic acid molecules encoding the MAP3K15predicted loss-of-function polypeptides have not been associated withmetabolic disorders, such as Type-2 diabetes. Moreover, theidentification by the present disclosure of the association betweenadditional variants and gene burden masks indicates that MAP3K15 itself(rather than linkage disequilibrium with variants in another gene) isresponsible for a protective effect in a metabolic disorder, such asType-2 diabetes. Therefore, subjects that are MAP3K15 reference orheterozygous for MAP3K15 missense variant nucleic acid moleculesencoding MAP3K15 predicted loss-of-function polypeptides may be treatedwith a MAP3K15 inhibitor such that metabolic disorder is inhibited orprevented, the symptoms thereof are reduced or prevented, and/ordevelopment of symptoms is repressed or prevented. It is also believedthat such subjects having a metabolic disorder may further be treatedwith therapeutic agents that treat or prevent the metabolic disorder.

For purposes of the present disclosure, any particular subject, such asa human, can be categorized as having one of three MAP3K15 genotypes: i)MAP3K15 reference; ii) heterozygous for MAP3K15 missense variant nucleicacid molecules encoding MAP3K15 predicted loss-of-function polypeptides;or iii) homozygous for MAP3K15 missense variant nucleic acid moleculesencoding MAP3K15 predicted loss-of-function polypeptides. A subject isMAP3K15 reference when the subject does not have a copy of a MAP3K15missense variant nucleic acid molecules encoding a MAP3K15 predictedloss-of-function polypeptide. A subject is heterozygous for a MAP3K15missense variant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide when the subject has a single copy of aMAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide. A MAP3K15 missense variantnucleic acid molecule encoding a MAP3K15 predicted loss-of-functionpolypeptide is any nucleic acid molecule (such as, a genomic nucleicacid molecule, an mRNA molecule, or a cDNA molecule) encoding a variantMAP3K15 polypeptide having a partial loss-of-function, a completeloss-of-function, a predicted partial loss-of-function, or a predictedcomplete loss-of-function. A subject who has a MAP3K15 polypeptidehaving a partial loss-of-function (or predicted partialloss-of-function) is hypomorphic for MAP3K15. A subject is homozygousfor MAP3K15 missense variant nucleic acid molecules encoding MAP3K15predicted loss-of-function polypeptides when the subject has two copies(same or different) of a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide.

For subjects that are genotyped or determined to be MAP3K15 reference,such subjects have an increased risk of developing a metabolic disorder,such as Type-2 diabetes, increased hemoglobin A1c, or increased serumglucose. For subjects that are genotyped or determined to be eitherMAP3K15 reference or heterozygous for a MAP3K15 missense variant nucleicacid molecule encoding a MAP3K15 predicted loss-of-function polypeptide,such subjects can be treated with a MAP3K15 inhibitor.

In any of the embodiments described herein, the MAP3K15 missense variantnucleic acid molecules encoding MAP3K15 predicted loss-of-functionpolypeptides can be any nucleic acid molecule (such as, for example,genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) encodinga MAP3K15 variant polypeptide having a partial loss-of-function, acomplete loss-of-function, a predicted partial loss-of-function, or apredicted complete loss-of-function. In some embodiments, the MAP3K15missense variant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide is associated with a reduced in vitroresponse to MAP3K15 ligands compared with reference MAP3K15. In someembodiments, the MAP3K15 missense variant nucleic acid molecule encodingthe MAP3K15 predicted loss-of-function polypeptide is a MAP3K15 variantthat results or is predicted to result in a premature truncation of aMAP3K15 polypeptide compared to the human reference genome sequence. Insome embodiments, the MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide is a variantthat is predicted to be damaging by in vitro prediction algorithms suchas Polyphen, SIFT, or similar algorithms. In some embodiments, theMAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide is a variant that causes or ispredicted to cause a nonsynonymous amino-acid substitution in MAP3K15and whose allele frequency is less than 1/100 alleles in the populationfrom which the subject is selected. In some embodiments, the MAP3K15missense variant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide is any rare missense variant (allelefrequency<0.1%; or 1 in 1,000 alleles), or any splice-site, stop-gain,start-loss, stop-loss, frameshift, or in-frame indel, or otherframeshift MAP3K15 variant.

In any of the embodiments described herein, the MAP3K15 predictedloss-of-function polypeptide can be any MAP3K15 polypeptide having apartial loss-of-function, a complete loss-of-function, a predictedpartial loss-of-function, or a predicted complete loss-of-function.

In any of the embodiments described herein, the MAP3K15 missense variantnucleic acid molecule encoding a MAP3K15 predicted loss-of-functionpolypeptide can include variations at any positions of the X chromosomeusing the nucleotide sequence of the MAP3K15 reference genomic nucleicacid molecule (SEQ ID NO:1; ENSG00000180815.14 in the GRCh38/hg38 humangenome assembly) as a reference sequence.

Any one or more (i.e., any combination) of MAP3K15 missense variantnucleic acid molecules encoding MAP3K15 predicted loss-of-functionpolypeptides can be used within any of the methods described herein todetermine whether a subject has an increased risk of developing ametabolic disorder, such as Type-2 diabetes. The combinations ofparticular variants can form a mask used for statistical analysis of theparticular correlation of MAP3K15 and decreased risk of developing ametabolic disorder, such as Type-2 diabetes.

In any of the embodiments described herein, the metabolic disorder isType-2 diabetes, increased hemoglobin A1c, or increased serum glucose.In some embodiments, the metabolic disorder is Type-2 diabetes. In someembodiments, the metabolic disorder is increased hemoglobin A1c. In someembodiments, the metabolic disorder is increased serum glucose.

Symptoms of Type-2 diabetes include, but are not limited to, any one ormore of high blood sugar, insulin resistance, and low insulin levels, orany combination thereof. In some embodiments, the Type-2 diabetessymptoms further comprise polyuria, polydipsia, polyphagia, weight loss,blurred vision, itchiness, peripheral neuropathy, recurrent vaginalinfections, and fatigue, or any combination thereof.

The present disclosure provides methods of treating a subject having ametabolic disorder or at risk of developing a metabolic disorder, themethods comprising administering a MAP3K15 inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving Type-2 diabetes or at risk of developing Type-2 diabetes, themethods comprising administering a MAP3K15 inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving increased hemoglobin A1c or at risk of developing increasedhemoglobin A1c, the methods comprising administering a MAP3K15 inhibitorto the subject.

The present disclosure also provides methods of treating a subjecthaving increased serum glucose or at risk of developing increased serumglucose, the methods comprising administering a MAP3K15 inhibitor to thesubject.

The present disclosure also provides methods of preventing a subjectfrom developing a metabolic disorder, the methods comprisingadministering a MAP3K15 inhibitor to the subject.

The present disclosure also provides methods of preventing a subjectfrom developing Type-2 diabetes, the methods comprising administering aMAP3K15 inhibitor to the subject.

The present disclosure also provides methods of preventing a subjectfrom developing increased hemoglobin A1c, the methods comprisingadministering a MAP3K15 inhibitor to the subject.

The present disclosure also provides methods of preventing a subjectfrom developing increased serum glucose, the methods comprisingadministering a MAP3K15 inhibitor to the subject.

In some embodiments, the MAP3K15 inhibitor comprises an inhibitorynucleic acid molecule. Examples of inhibitory nucleic acid moleculesinclude, but are not limited to, antisense nucleic acid molecules, smallinterfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Suchinhibitory nucleic acid molecules can be designed to target any regionof a MAP3K15 nucleic acid molecule. In some embodiments, the antisenseRNA, siRNA, or shRNA hybridizes to a sequence within a MAP3K15 genomicnucleic acid molecule or mRNA molecule and decreases expression of theMAP3K15 polypeptide in a cell in the subject. In some embodiments, theMAP3K15 inhibitor comprises an antisense molecule that hybridizes to aMAP3K15 genomic nucleic acid molecule or mRNA molecule and decreasesexpression of the MAP3K15 polypeptide in a cell in the subject. In someembodiments, the MAP3K15 inhibitor comprises an siRNA that hybridizes toa MAP3K15 genomic nucleic acid molecule or mRNA molecule and decreasesexpression of the MAP3K15 polypeptide in a cell in the subject. In someembodiments, the MAP3K15 inhibitor comprises an shRNA that hybridizes toa MAP3K15 genomic nucleic acid molecule or mRNA molecule and decreasesexpression of the MAP3K15 polypeptide in a cell in the subject.

The inhibitory nucleic acid molecules can comprise RNA, DNA, or both RNAand DNA. The inhibitory nucleic acid molecules can also be linked orfused to a heterologous nucleic acid sequence, such as in a vector, or aheterologous label. For example, the inhibitory nucleic acid moleculescan be within a vector or as an exogenous donor sequence comprising theinhibitory nucleic acid molecule and a heterologous nucleic acidsequence. The inhibitory nucleic acid molecules can also be linked orfused to a heterologous label. The label can be directly detectable(such as, for example, fluorophore) or indirectly detectable (such as,for example, hapten, enzyme, or fluorophore quencher). Such labels canbe detectable by spectroscopic, photochemical, biochemical,immunochemical, or chemical means. Such labels include, for example,radiolabels, pigments, dyes, chromogens, spin labels, and fluorescentlabels. The label can also be, for example, a chemiluminescentsubstance; a metal-containing substance; or an enzyme, where thereoccurs an enzyme-dependent secondary generation of signal. The term“label” can also refer to a “tag” or hapten that can bind selectively toa conjugated molecule such that the conjugated molecule, when addedsubsequently along with a substrate, is used to generate a detectablesignal. For example, biotin can be used as a tag along with an avidin orstreptavidin conjugate of horseradish peroxidate (HRP) to bind to thetag, and examined using a calorimetric substrate (such as, for example,tetramethylbenzidine (TMB)) or a fluorogenic substrate to detect thepresence of HRP. Exemplary labels that can be used as tags to facilitatepurification include, but are not limited to, myc, HA, FLAG or 3×FLAG,6×His or polyhistidine, glutathione-S-transferase (GST), maltose bindingprotein, an epitope tag, or the Fc portion of immunoglobulin. Numerouslabels include, for example, particles, fluorophores, haptens, enzymesand their calorimetric, fluorogenic and chemiluminescent substrates andother labels.

The inhibitory nucleic acid molecules can comprise, for example,nucleotides or non-natural or modified nucleotides, such as nucleotideanalogs or nucleotide substitutes. Such nucleotides include a nucleotidethat contains a modified base, sugar, or phosphate group, or thatincorporates a non-natural moiety in its structure. Examples ofnon-natural nucleotides include, but are not limited to,dideoxynucleotides, biotinylated, aminated, deaminated, alkylated,benzylated, and fluorophor-labeled nucleotides.

The inhibitory nucleic acid molecules can also comprise one or morenucleotide analogs or substitutions. A nucleotide analog is a nucleotidewhich contains a modification to either the base, sugar, or phosphatemoieties. Modifications to the base moiety include, but are not limitedto, natural and synthetic modifications of A, C, G, and T/U, as well asdifferent purine or pyrimidine bases such as, for example,pseudouridine, uracil-5-yl, hypoxanthin-9-yl (I), and2-aminoadenin-9-yl. Modified bases include, but are not limited to,5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine,hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives ofadenine and guanine, 2-propyl and other alkyl derivatives of adenine andguanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouraciland cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine andthymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino,8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines andguanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl andother 5-substituted uracils and cytosines, 7-methylguanine,7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine,7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

Nucleotide analogs can also include modifications of the sugar moiety.Modifications to the sugar moiety include, but are not limited to,natural modifications of the ribose and deoxy ribose as well assynthetic modifications. Sugar modifications include, but are notlimited to, the following modifications at the 2′ position: OH; F; O-,S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; orO-alkyl-O-alkyl, wherein the alkyl, alkenyl, and alkynyl may besubstituted or unsubstituted C₁₋₁₀alkyl or C₂₋₁₀alkenyl, andC₂₋₁₀alkynyl. Exemplary 2′ sugar modifications also include, but are notlimited to, —O[(CH₂)_(n)O]_(m)CH₃, —O(CH₂)_(n)OCH₃, —O(CH₂)_(n)NH₂,—O(CH₂)_(n)CH₃, —O(CH₂)_(n)—ONH₂, and —O(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂,where n and m, independently, are from 1 to about 10. Othermodifications at the 2′ position include, but are not limited to,C₁₋₁₀alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl orO-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂,NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,polyalkylamino, substituted silyl, an RNA cleaving group, a reportergroup, an intercalator, a group for improving the pharmacokineticproperties of an oligonucleotide, or a group for improving thepharmacodynamic properties of an oligonucleotide, and other substituentshaving similar properties. Similar modifications may also be made atother positions on the sugar, particularly the 3′ position of the sugaron the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides andthe 5′ position of 5′ terminal nucleotide. Modified sugars can alsoinclude those that contain modifications at the bridging ring oxygen,such as CH₂ and S. Nucleotide sugar analogs can also have sugarmimetics, such as cyclobutyl moieties in place of the pentofuranosylsugar.

Nucleotide analogs can also be modified at the phosphate moiety.Modified phosphate moieties include, but are not limited to, those thatcan be modified so that the linkage between two nucleotides contains aphosphorothioate, chiral phosphorothioate, phosphorodithioate,phosphotriester, aminoalkylphosphotriester, methyl and other alkylphosphonates including 3′-alkylene phosphonate and chiral phosphonates,phosphinates, phosphoramidates including 3′-amino phosphoramidate andaminoalkylphosphoramidates, thionophosphoramidates,thionoalkylphosphonates, thionoalkylphosphotriesters, andboranophosphates. These phosphate or modified phosphate linkage betweentwo nucleotides can be through a 3′-5′ linkage or a 2′-5′ linkage, andthe linkage can contain inverted polarity such as 3′-5′ to 5′-3′ or2′-5′ to 5′-2′. Various salts, mixed salts, and free acid forms are alsoincluded. Nucleotide substitutes also include peptide nucleic acids(PNAs).

In some embodiments, the antisense nucleic acid molecules are gapmers,whereby the first one to seven nucleotides at the 5′ and 3′ ends eachhave 2′-methoxyethyl (2′-MOE) modifications. In some embodiments, thefirst five nucleotides at the 5′ and 3′ ends each have 2′-MOEmodifications. In some embodiments, the first one to seven nucleotidesat the 5′ and 3′ ends are RNA nucleotides. In some embodiments, thefirst five nucleotides at the 5′ and 3′ ends are RNA nucleotides. Insome embodiments, each of the backbone linkages between the nucleotidesis a phosphorothioate linkage.

In some embodiments, the siRNA molecules have termini modifications. Insome embodiments, the 5′ end of the antisense strand is phosphorylated.In some embodiments, 5′-phosphate analogs that cannot be hydrolyzed,such as 5′-(E)-vinyl-phosphonate are used. In some embodiments, thesiRNA molecules have backbone modifications. In some embodiments, themodified phosphodiester groups that link consecutive ribose nucleosideshave been shown to enhance the stability and in vivo bioavailability ofsiRNAs The non-ester groups (—OH, ═O) of the phosphodiester linkage canbe replaced with sulfur, boron, or acetate to give phosphorothioate,boranophosphate, and phosphonoacetate linkages. In addition,substituting the phosphodiester group with a phosphotriester canfacilitate cellular uptake of siRNAs and retention on serum componentsby eliminating their negative charge. In some embodiments, the siRNAmolecules have sugar modifications. In some embodiments, the sugars aredeprotonated (reaction catalyzed by exo- and endonucleases) whereby the2′-hydroxyl can act as a nucleophile and attack the adjacent phosphorousin the phosphodiester bond. Such alternatives include 2′-O-methyl,2′-O-methoxyethyl, and 2′-fluoro modifications.

In some embodiments, the siRNA molecules have base modifications. Insome embodiments, the bases can be substituted with modified bases suchas pseudouridine, 5′-methylcytidine, N6-methyladenosine, inosine, andN7-methylguanosine.

In some embodiments, the siRNA molecules are conjugated to lipids.Lipids can be conjugated to the 5′ or 3′ termini of siRNA to improvetheir in vivo bioavailability by allowing them to associate with serumlipoproteins. Representative lipids include, but are not limited to,cholesterol and vitamin E, and fatty acids, such as palmitate andtocopherol.

In some embodiments, a representative siRNA has the following formula:

Sense:mN*mN*/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/*mN*/32FN/

Antisense:/52FN/*/i2FN/*mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN*N*N

wherein: “N” is the base; “2F” is a 2′-F modification; “m” is a2′-O-methyl modification, “I” is an internal base; and “*” is aphosphorothioate backbone linkage.

The present disclosure also provides vectors comprising any one or moreof the inhibitory nucleic acid molecules. In some embodiments, thevectors comprise any one or more of the inhibitory nucleic acidmolecules and a heterologous nucleic acid. The vectors can be viral ornonviral vectors capable of transporting a nucleic acid molecule. Insome embodiments, the vector is a plasmid or cosmid (such as, forexample, a circular double-stranded DNA into which additional DNAsegments can be ligated). In some embodiments, the vector is a viralvector, wherein additional DNA segments can be ligated into the viralgenome. Expression vectors include, but are not limited to, plasmids,cosmids, retroviruses, adenoviruses, adeno-associated viruses (AAV),plant viruses such as cauliflower mosaic virus and tobacco mosaic virus,yeast artificial chromosomes (YACs), Epstein-Barr (EBV)-derivedepisomes, and other expression vectors known in the art.

The present disclosure also provides compositions comprising any one ormore of the inhibitory nucleic acid molecules. In some embodiments, thecomposition is a pharmaceutical composition. In some embodiments, thecompositions comprise a carrier and/or excipient. Examples of carriersinclude, but are not limited to, poly(lactic acid) (PLA) microspheres,poly(D,L-lactic-coglycolic-acid) (PLGA) microspheres, liposomes,micelles, inverse micelles, lipid cochleates, and lipid microtubules. Acarrier may comprise a buffered salt solution such as PBS, HBSS, etc.

In some embodiments, the MAP3K15 inhibitor comprises a nuclease agentthat induces one or more nicks or double-strand breaks at a recognitionsequence(s) or a DNA-binding protein that binds to a recognitionsequence within a MAP3K15 genomic nucleic acid molecule. The recognitionsequence can be located within a coding region of the MAP3K15 gene, orwithin regulatory regions that influence the expression of the gene. Arecognition sequence of the DNA-binding protein or nuclease agent can belocated in an intron, an exon, a promoter, an enhancer, a regulatoryregion, or any non-protein coding region. The recognition sequence caninclude or be proximate to the start codon of the MAP3K15 gene. Forexample, the recognition sequence can be located about 10, about 20,about 30, about 40, about 50, about 100, about 200, about 300, about400, about 500, or about 1,000 nucleotides from the start codon. Asanother example, two or more nuclease agents can be used, each targetinga nuclease recognition sequence including or proximate to the startcodon. As another example, two nuclease agents can be used, onetargeting a nuclease recognition sequence including or proximate to thestart codon, and one targeting a nuclease recognition sequence includingor proximate to the stop codon, wherein cleavage by the nuclease agentscan result in deletion of the coding region between the two nucleaserecognition sequences. Any nuclease agent that induces a nick ordouble-strand break into a desired recognition sequence can be used inthe methods and compositions disclosed herein. Any DNA-binding proteinthat binds to a desired recognition sequence can be used in the methodsand compositions disclosed herein.

Suitable nuclease agents and DNA-binding proteins for use hereininclude, but are not limited to, zinc finger protein or zinc fingernuclease (ZFN) pair, Transcription Activator-Like Effector (TALE)protein or Transcription Activator-Like Effector Nuclease (TALEN), orClustered Regularly Interspersed Short Palindromic Repeats(CRISPR)/CRISPR-associated (Cas) systems. The length of the recognitionsequence can vary, and includes, for example, recognition sequences thatare about 30-36 bp for a zinc finger protein or ZFN pair, about 15-18 bpfor each ZFN, about 36 bp for a TALE protein or TALEN, and about 20 bpfor a CRISPR/Cas guide RNA.

In some embodiments, CRISPR/Cas systems can be used to modify a MAP3K15genomic nucleic acid molecule within a cell. The methods andcompositions disclosed herein can employ CRISPR-Cas systems by utilizingCRISPR complexes (comprising a guide RNA (gRNA) complexed with a Casprotein) for site-directed cleavage of MAP3K15 nucleic acid molecules.

Cas proteins generally comprise at least one RNA recognition or bindingdomain that can interact with gRNAs. Cas proteins can also comprisenuclease domains (such as, for example, DNase or RNase domains), DNAbinding domains, helicase domains, protein-protein interaction domains,dimerization domains, and other domains. Suitable Cas proteins include,for example, a wild type Cas9 protein and a wild type Cpf1 protein (suchas, for example, FnCpf1). A Cas protein can have full cleavage activityto create a double-strand break in a MAP3K15 genomic nucleic acidmolecule or it can be a nickase that creates a single-strand break in aMAP3K15 genomic nucleic acid molecule. Additional examples of Casproteins include, but are not limited to, Cas1, Cas1B, Cast, Cas3, Cas4,Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1, Cas8a2, Cas8b,Cas8c, Cas9 (Csn1 or Csx12), Cas10, Cas10d, CasF, CasG, CasH, Csyl,Csy2, Csy3, Cse1 (CasA), Cse2 (Cas6), Cse3 (CasE), Cse4 (CasC), Csc1,Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cnnr1, Cmr3, Cmr4, Cmr5,Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1,Csx15, Csf1, Csf2, Csf3, Csf4, and Cu1966, and homologs or modifiedversions thereof. Cas proteins can also be operably linked toheterologous polypeptides as fusion proteins. For example, a Cas proteincan be fused to a cleavage domain, an epigenetic modification domain, atranscriptional activation domain, or a transcriptional repressordomain. Cas proteins can be provided in any form. For example, a Casprotein can be provided in the form of a protein, such as a Cas proteincomplexed with a gRNA. Alternately, a Cas protein can be provided in theform of a nucleic acid molecule encoding the Cas protein, such as an RNAor DNA.

In some embodiments, targeted genetic modifications of MAP3K15 genomicnucleic acid molecules can be generated by contacting a cell with a Casprotein and one or more gRNAs that hybridize to one or more gRNArecognition sequences within a target genomic locus in the MAP3K15genomic nucleic acid molecule. For example, a gRNA recognition sequencecan be located within a region of SEQ ID NO:1. The gRNA recognitionsequence can include or be proximate to the start codon of a MAP3K15genomic nucleic acid molecule or the stop codon of a MAP3K15 genomicnucleic acid molecule. For example, the gRNA recognition sequence can belocated from about 10, from about 20, from about 30, from about 40, fromabout 50, from about 100, from about 200, from about 300, from about400, from about 500, or from about 1,000 nucleotides of the start codonor the stop codon.

The gRNA recognition sequences within a target genomic locus in aMAP3K15 genomic nucleic acid molecule are located near a ProtospacerAdjacent Motif (PAM) sequence, which is a 2-6 base pair DNA sequenceimmediately following the DNA sequence targeted by the Cas9 nuclease.The canonical PAM is the sequence 5′-NGG-3′ where “N” is any nucleobasefollowed by two guanine (“G”) nucleobases. gRNAs can transport Cas9 toanywhere in the genome for gene editing, but no editing can occur at anysite other than one at which Cas9 recognizes PAM. In addition, 5′-NGA-3′can be a highly efficient non-canonical PAM for human cells. Generally,the PAM is about 2-6 nucleotides downstream of the DNA sequence targetedby the gRNA. The PAM can flank the gRNA recognition sequence. In someembodiments, the gRNA recognition sequence can be flanked on the 3′ endby the PAM. In some embodiments, the gRNA recognition sequence can beflanked on the 5′ end by the PAM. For example, the cleavage site of Casproteins can be about 1 to about 10, about 2 to about 5 base pairs, orthree base pairs upstream or downstream of the PAM sequence. In someembodiments (such as when Cas9 from S. pyogenes or a closely relatedCas9 is used), the PAM sequence of the non-complementary strand can be5′-NGG-3′, where N is any DNA nucleotide and is immediately 3′ of thegRNA recognition sequence of the non-complementary strand of the targetDNA. As such, the PAM sequence of the complementary strand would be5′-CCN-3′, where N is any DNA nucleotide and is immediately 5′ of thegRNA recognition sequence of the complementary strand of the target DNA.

A gRNA is an RNA molecule that binds to a Cas protein and targets theCas protein to a specific location within a MAP3K15 genomic nucleic acidmolecule. An exemplary gRNA is a gRNA effective to direct a Cas enzymeto bind to or cleave a MAP3K15 genomic nucleic acid molecule, whereinthe gRNA comprises a DNA-targeting segment that hybridizes to a gRNArecognition sequence within the MAP3K15 genomic nucleic acid molecule.Exemplary gRNAs comprise a DNA-targeting segment that hybridizes to agRNA recognition sequence present within a MAP3K15 genomic nucleic acidmolecule that includes or is proximate to the start codon or the stopcodon. For example, a gRNA can be selected such that it hybridizes to agRNA recognition sequence that is located from about 5, from about 10,from about 15, from about 20, from about 25, from about 30, from about35, from about 40, from about 45, from about 50, from about 100, fromabout 200, from about 300, from about 400, from about 500, or from about1,000 nucleotides of the start codon or located from about 5, from about10, from about 15, from about 20, from about 25, from about 30, fromabout 35, from about 40, from about 45, from about 50, from about 100,from about 200, from about 300, from about 400, from about 500, or fromabout 1,000 nucleotides of the stop codon. Suitable gRNAs can comprisefrom about 17 to about 25 nucleotides, from about 17 to about 23nucleotides, from about 18 to about 22 nucleotides, or from about 19 toabout 21 nucleotides. In some embodiments, the gRNAs can comprise 20nucleotides.

Examples of suitable gRNA recognition sequences located within the humanMAP3K15 reference gene are set forth in Table 1 as SEQ ID NOs:19-38.

TABLE 1 Guide RNA Recognition Sequences Within the MAP3K15 Gene StrandgRNA Recognition Sequence SEQ ID NO: − TGATCGGCCAAATCACACGT 19 +GCACCTGAGATAATTGACCA 20 + ATGGTGAGAGAGTTGTCTTG 21 − TCACCAAGCTCATGGAACGG22 − GAACCTCAGTATTATCCATG 23 − GGCAGATGGGAATTACCATG 24 +GGTGAACACCTACAGCGGAG 25 + CAATACAGCAGGCAGTACGG 26 − GGAATTACCATGAGGTCACG27 − CAGCAAAAATAATCAGCGCA 28 + ATAATTGACCAAGGGCCTCG 29 +AGTCCGAGAAAGCTTTGACA 30 + CGAGTACATGCAGCCCAACT 31 − TCCACCAAAGGCATGCACAG32 − GCTGAGGGTTTACCACTCAA 33 + CTCTTCTGCGATCCAAATGG 34 +CCAACAGGACTATGATGCGA 35 − AGTTCTGAACTAATGATCGC 36 + TTCCATAAACAATGAAGCCG37 + GTGCGCAGTGAGAGCTCCCA 38

The Cas protein and the gRNA form a complex, and the Cas protein cleavesthe target MAP3K15 genomic nucleic acid molecule. The Cas protein cancleave the nucleic acid molecule at a site within or outside of thenucleic acid sequence present in the target MAP3K15 genomic nucleic acidmolecule to which the DNA-targeting segment of a gRNA will bind. Forexample, formation of a CRISPR complex (comprising a gRNA hybridized toa gRNA recognition sequence and complexed with a Cas protein) can resultin cleavage of one or both strands in or near (such as, for example,within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from)the nucleic acid sequence present in the MAP3K15 genomic nucleic acidmolecule to which a DNA-targeting segment of a gRNA will bind.

Such methods can result, for example, in a MAP3K15 genomic nucleic acidmolecule in which a region of SEQ ID NO:1 is disrupted, the start codonis disrupted, the stop codon is disrupted, or the coding sequence isdisrupted or deleted. Optionally, the cell can be further contacted withone or more additional gRNAs that hybridize to additional gRNArecognition sequences within the target genomic locus in the MAP3K15genomic nucleic acid molecule. By contacting the cell with one or moreadditional gRNAs (such as, for example, a second gRNA that hybridizes toa second gRNA recognition sequence), cleavage by the Cas protein cancreate two or more double-strand breaks or two or more single-strandbreaks.

In some embodiments, the methods of treatment or prevention furthercomprise detecting the presence or absence of a MAP3K15 missense variantnucleic acid molecule encoding a MAP3K15 predicted loss-of-functionpolypeptide in a biological sample from the subject. As used throughoutthe present disclosure, a “MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide” isany MAP3K15 nucleic acid molecule (such as, for example, genomic nucleicacid molecule, mRNA molecule, or cDNA molecule) encoding a MAP3K15polypeptide having a partial loss-of-function, a completeloss-of-function, a predicted partial loss-of-function, or a predictedcomplete loss-of-function.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or prevents a metabolic disorder,wherein the subject has the metabolic disorder or is at risk ofdeveloping the metabolic disorder. In some embodiments, the subject hasthe metabolic disorder. In some embodiments, the subject is at risk ofdeveloping the metabolic disorder. The present disclosure also providesmethods of preventing a subject from developing a metabolic disorder byadministering a therapeutic agent that prevents the metabolic disorder.In some embodiments, the methods comprise determining whether thesubject has a MAP3K15 missense variant nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide by obtaining or havingobtained a biological sample from the subject, and performing or havingperformed a sequence analysis on the biological sample to determine ifthe subject has a genotype comprising the MAP3K15 missense variantnucleic acid molecule encoding the MAP3K15 predicted loss-of-functionpolypeptide. In some embodiments, the methods further compriseadministering or continuing to administer the therapeutic agent thattreats or prevents the metabolic disorder in a standard dosage amount toa subject that is MAP3K15 reference, and/or administering a MAP3K15inhibitor to the subject. In some embodiments, the methods furthercomprise administering or continuing to administer the therapeutic agentthat treats or prevents the metabolic disorder in an amount that is thesame as or less than a standard dosage amount to a subject that isheterozygous for the MAP3K15 missense variant nucleic acid molecule,and/or administering a MAP3K15 inhibitor to the subject. In someembodiments, the methods further comprise administering or continuing toadminister the therapeutic agent that treats or prevents the metabolicdisorder in an amount that is the same as or less than a standard dosageamount to a subject that is homozygous for the MAP3K15 missense variantnucleic acid molecule. The presence of a genotype having the MAP3K15missense variant nucleic acid molecule encoding the MAP3K15 predictedloss-of-function polypeptide indicates the subject has a decreased riskof developing the metabolic disorder, such as Type-2 diabetes. In someembodiments, the subject is MAP3K15 reference. In some embodiments, thesubject is heterozygous for a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide.

For subjects that are genotyped or determined to be either MAP3K15reference or heterozygous for a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide, suchsubjects can be administered a MAP3K15 inhibitor, as described herein.

Detecting the presence or absence of a MAP3K15 missense variant nucleicacid molecule encoding a MAP3K15 predicted loss-of-function polypeptidein a biological sample from a subject and/or determining whether asubject has a MAP3K15 missense variant nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide can be carried out by anyof the methods described herein. In some embodiments, these methods canbe carried out in vitro. In some embodiments, these methods can becarried out in situ. In some embodiments, these methods can be carriedout in vivo. In any of these embodiments, the nucleic acid molecule canbe present within a cell obtained from the subject.

In some embodiments, when the subject is MAP3K15 reference, the subjectis administered a therapeutic agent that treats or prevents a metabolicdisorder in a standard dosage amount. In some embodiments, when thesubject is heterozygous for a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide, thesubject is administered a therapeutic agent that treats or prevents ametabolic disorder in a dosage amount that is the same as or less than astandard dosage amount.

In some embodiments, the treatment or prevention methods furthercomprise detecting the presence or absence of a MAP3K15 predictedloss-of-function polypeptide in a biological sample from the subject. Insome embodiments, when the subject does not have a MAP3K15 predictedloss-of-function polypeptide, the subject is administered a therapeuticagent that treats or prevents a metabolic disorder in a standard dosageamount. In some embodiments, when the subject has a MAP3K15 predictedloss-of-function polypeptide, the subject is administered a therapeuticagent that treats or prevents a metabolic disorder in a dosage amountthat is the same as or less than a standard dosage amount.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or prevents a metabolic disorder,wherein the subject has the metabolic disorder or is at risk ofdeveloping a metabolic disorder. In some embodiments, the methodcomprises determining whether the subject has a MAP3K15 predictedloss-of-function polypeptide by obtaining or having obtained abiological sample from the subject, and performing or having performedan assay on the biological sample to determine if the subject has aMAP3K15 predicted loss-of-function polypeptide. When the subject doesnot have a MAP3K15 predicted loss-of-function polypeptide, thetherapeutic agent that treats or prevents the metabolic disorder isadministered or continued to be administered to the subject in astandard dosage amount, and/or a MAP3K15 inhibitor is administered tothe subject. When the subject has a MAP3K15 predicted loss-of-functionpolypeptide, the therapeutic agent that treats or prevents the metabolicdisorder is administered or continued to be administered to the subjectin an amount that is the same as or less than a standard dosage amount,and/or a MAP3K15 inhibitor is administered to the subject. The presenceof a MAP3K15 predicted loss-of-function polypeptide indicates thesubject has a decreased risk of developing the metabolic disorder. Insome embodiments, the subject has a MAP3K15 predicted loss-of-functionpolypeptide. In some embodiments, the subject does not have a MAP3K15predicted loss-of-function polypeptide.

The present disclosure also provides methods of preventing a subjectfrom developing a metabolic disorder by administering a therapeuticagent that prevents the metabolic disorder. In some embodiments, themethod comprises determining whether the subject has a MAP3K15 predictedloss-of-function polypeptide by obtaining or having obtained abiological sample from the subject, and performing or having performedan assay on the biological sample to determine if the subject has aMAP3K15 predicted loss-of-function polypeptide. When the subject doesnot have a MAP3K15 predicted loss-of-function polypeptide, thetherapeutic agent that prevents the metabolic disorder is administeredor continued to be administered to the subject in a standard dosageamount, and/or a MAP3K15 inhibitor is administered to the subject. Whenthe subject has a MAP3K15 predicted loss-of-function polypeptide, thetherapeutic agent that prevents the metabolic disorder is administeredor continued to be administered to the subject in an amount that is thesame as or less than a standard dosage amount, and/or a MAP3K15inhibitor is administered to the subject. The presence of a MAP3K15predicted loss-of-function polypeptide indicates the subject has adecreased risk of developing the metabolic disorder. In someembodiments, the subject has a MAP3K15 predicted loss-of-functionpolypeptide. In some embodiments, the subject does not have a MAP3K15predicted loss-of-function polypeptide.

Detecting the presence or absence of a MAP3K15 predictedloss-of-function polypeptide in a biological sample from a subjectand/or determining whether a subject has a MAP3K15 predictedloss-of-function polypeptide can be carried out by any of the methodsdescribed herein. In some embodiments, these methods can be carried outin vitro. In some embodiments, these methods can be carried out in situ.In some embodiments, these methods can be carried out in vivo. In any ofthese embodiments, the polypeptide can be present within a cell obtainedfrom the subject.

In some embodiments, the MAP3K15 inhibitor is a small molecule. In someembodiments, the MAP3K15 inhibitor is staurosporine, lestaurtinib,NVP-TAE684, ruxolitinib, SU-14813, sunitinib, JNJ-28312141, crizotinib,linifanib, quizartinib, axitinib, motesanib, AST-487, AT-7519,barasertib-hQPA, cediranib, selumetinib, BI-2536, afatinib, doramapimod,BMS-345541, BMS-387032, brivanib, CHIR-265, canertinib, CI-1040,tofacitinib, dasatinib, foretinib, alvocidib, GDC-0879, pictilisib,GSK-1838705A, GSK-461364A, GW-2580, neratinib, imatinib, Ki-20227,KW-2449, lapatinib, enzastaurin, MLN-120B, tandutinib, MLN-8054,nilotinib, pazopanib, PD-173955, PHA-665752, PI-103, midostaurin,PLX-4720, vatalanib, tamatinib, R547, SGX-523, bosutinib, sorafenib,TG-100-115, fedratinib, vandetanib, tozasertib, neflamapimod, dovitinib,erlotinib, gefitinib, GSK690693, ruboxistaurin, SB203580, A-674563, ormasitinib. In some embodiments, the MAP3K15 inhibitor is staurosporine,lestaurtinib, NVP-TAE684, ruxolitinib, SU-14813, sunitinib,JNJ-28312141, crizotinib, SB203580, or ruboxistaurin. In someembodiments, the MAP3K15 inhibitor is staurosporine. In someembodiments, the MAP3K15 inhibitor is lestaurtinib. In some embodiments,the MAP3K15 inhibitor is NVP-TAE684. In some embodiments, the MAP3K15inhibitor is ruxolitinib. In some embodiments, the MAP3K15 inhibitor isSU-14813. In some embodiments, the MAP3K15 inhibitor is sunitinib. Insome embodiments, the MAP3K15 inhibitor is JNJ-28312141. In someembodiments, the MAP3K15 inhibitor is crizotinib. In some embodiments,the MAP3K15 inhibitor is linifanib. In some embodiments, the MAP3K15inhibitor is quizartinib. In some embodiments, the MAP3K15 inhibitor isaxitinib. In some embodiments, the MAP3K15 inhibitor is motesanib. Insome embodiments, the MAP3K15 inhibitor is AST-487. In some embodiments,the MAP3K15 inhibitor is AT-7519. In some embodiments, the MAP3K15inhibitor is barasertib-hQPA. In some embodiments, the MAP3K15 inhibitoris cediranib. In some embodiments, the MAP3K15 inhibitor is selumetinib.In some embodiments, the MAP3K15 inhibitor is BI-2536. In someembodiments, the MAP3K15 inhibitor is afatinib. In some embodiments, theMAP3K15 inhibitor is doramapimod. In some embodiments, the MAP3K15inhibitor is BMS-345541. In some embodiments, the MAP3K15 inhibitor isBMS-387032. In some embodiments, the MAP3K15 inhibitor is brivanib. Insome embodiments, the MAP3K15 inhibitor is CHIR-265. In someembodiments, the MAP3K15 inhibitor is canertinib. In some embodiments,the MAP3K15 inhibitor is CI-1040. In some embodiments, the MAP3K15inhibitor is tofacitinib. In some embodiments, the MAP3K15 inhibitor isdasatinib. In some embodiments, the MAP3K15 inhibitor is foretinib. Insome embodiments, the MAP3K15 inhibitor is alvocidib. In someembodiments, the MAP3K15 inhibitor is GDC-0879. In some embodiments, theMAP3K15 inhibitor is pictilisib. In some embodiments, the MAP3K15inhibitor is GSK-1838705A. In some embodiments, the MAP3K15 inhibitor isGSK-461364A. In some embodiments, the MAP3K15 inhibitor is GW-2580. Insome embodiments, the MAP3K15 inhibitor is neratinib. In someembodiments, the MAP3K15 inhibitor is imatinib. In some embodiments, theMAP3K15 inhibitor is Ki-20227. In some embodiments, the MAP3K15inhibitor is KW-2449. In some embodiments, the MAP3K15 inhibitor islapatinib. In some embodiments, the MAP3K15 inhibitor is enzastaurin. Insome embodiments, the MAP3K15 inhibitor is MLN-120B. In someembodiments, the MAP3K15 inhibitor is tandutinib. In some embodiments,the MAP3K15 inhibitor is MLN-8054. In some embodiments, the MAP3K15inhibitor is nilotinib. In some embodiments, the MAP3K15 inhibitor ispazopanib. In some embodiments, the MAP3K15 inhibitor is PD-173955. Insome embodiments, the MAP3K15 inhibitor is PHA-665752. In someembodiments, the MAP3K15 inhibitor is PI-103. In some embodiments, theMAP3K15 inhibitor is midostaurin. In some embodiments, the MAP3K15inhibitor is PLX-4720. In some embodiments, the MAP3K15 inhibitor isvatalanib. In some embodiments, the MAP3K15 inhibitor is tamatinib. Insome embodiments, the MAP3K15 inhibitor is R547. In some embodiments,the MAP3K15 inhibitor is SGX-523 In some embodiments, the MAP3K15inhibitor is bosutinib. In some embodiments, the MAP3K15 inhibitor issorafenib. In some embodiments, the MAP3K15 inhibitor is TG-100-115. Insome embodiments, the MAP3K15 inhibitor is fedratinib. In someembodiments, the MAP3K15 inhibitor is vandetanib. In some embodiments,the MAP3K15 inhibitor is tozasertib. In some embodiments, the MAP3K15inhibitor is neflamapimod. In some embodiments, the MAP3K15 inhibitor isdovitinib. In some embodiments, the MAP3K15 inhibitor is erlotinib. Insome embodiments, the MAP3K15 inhibitor is gefitinib. In someembodiments, the MAP3K15 inhibitor is GSK690693. In some embodiments,the MAP3K15 inhibitor is ruboxistaurin. In some embodiments, the MAP3K15inhibitor is SB203580. In some embodiments, the MAP3K15 inhibitor isA-674563. In some embodiments, the MAP3K15 inhibitor is masitinib.

Examples of therapeutic agents that treat or prevent Type-2 diabetes,treat or prevent increased hemoglobin A1c include, and/or treat orprevent increased serum glucose include, but are not limited to:metformin, insulin, sulfonylureas (such as glyburide, glipizide, andglimepiride), meglitinides (such as repaglinide and nateglinide),thiazolidinediones (such as rosiglitazone and pioglitazone), DPP-4inhibitors (such as sitagliptin, saxagliptin, and linagliptin), GLP-1receptor agonists (such as exenatide, liraglutide, and semaglutide), andSGLT2 inhibitors (such as canagliflozin, dapagliflozin, andempagliflozin). In some embodiments, the therapeutic agent is metformin,insulin, glyburide, glipizide, glimepiride, repaglinide, nateglinide,rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin,exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, orempagliflozin. In some embodiments, the therapeutic agent is metformin.In some embodiments, the therapeutic agent is insulin. In someembodiments, the therapeutic agent is glyburide. In some embodiments,the therapeutic agent is glipizide. In some embodiments, the therapeuticagent is glimepiride. In some embodiments, the therapeutic agent isrepaglinide. In some embodiments, the therapeutic agent is nateglinide.In some embodiments, the therapeutic agent is rosiglitazone. In someembodiments, the therapeutic agent is pioglitazone. In some embodiments,the therapeutic agent is sitagliptin. In some embodiments, thetherapeutic agent is saxagliptin. In some embodiments, the therapeuticagent is linagliptin. In some embodiments, the therapeutic agent isexenatide. In some embodiments, the therapeutic agent is liraglutide. Insome embodiments, the therapeutic agent is semaglutide. In someembodiments, the therapeutic agent is canagliflozin. In someembodiments, the therapeutic agent is dapagliflozin. In someembodiments, the therapeutic agent is empagliflozin.

In some embodiments, the therapeutic agent is GLUCOPHAGE® or GLUMETZA®(metformin), a sulfonylurea (DIABETA® or GLYNASE® (glyburide),GLUCOTROL® (glipizide), and AMARYL® (glimepiride)), a meglitinide(PRANDIN® (repaglinide) and STARLIX® (nateglinide)), athiazolidinediones (AVANDIA® (rosiglitazone) and ACTOS® (pioglitazone)),a dipeptidyl peptidase-4 (DPP-4) inhibitor (JANUVIA® (sitagliptin),ONGLYZA® (saxagliptin) and TRADJENTA® (linagliptin)), a glucagon-likepeptide-1 (GLP-1) receptor agonist (BYETTA® (exenatide) and VICTOZA®(liraglutide)), an SGLT2 inhibitor (INVOKANA® (canagliflozin) andFARXIGA® (dapagliflozin)), or APIDRA® (insulin glulisine), HUMALOG®(insulin lispro), NOVOLOG® (insulin aspart), LANTUS® (insulin glargine),LEVEMIR® (insulin detemir), or HUMULIN® N or NOVOLIN® N (insulinisophane), PRALUENT® (alirocumab), or any combination thereof. In someembodiments, the therapeutic agent is PRALUENT® (alirocumab).

In some embodiments, the therapeutic agent is metformin, a sulfonylurea(glyburide, glipizide, or glimepiride), a meglitinide (repaglinide ornateglinide), a thiazolidinediones (rosiglitazone or pioglitazone), adipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin, saxagliptin, orlinagliptin), a glucagon-like peptide-1 (GLP-1) receptor agonist(exenatide or liraglutide), an SGLT2 inhibitor (canagliflozin ordapagliflozin), or an insulin (glulisine, insulin lispro, insulinaspart, insulin glargine, insulin detemir, or insulin isophane), oralirocumab, or any combination thereof. In some embodiments, thetherapeutic agent is alirocumab.

In some embodiments, the dose of the therapeutic agents that treat orprevent a metabolic disorder can be decreased by about 10%, by about20%, by about 30%, by about 40%, by about 50%, by about 60%, by about70%, by about 80%, or by about 90% for subjects that are heterozygousfor a MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide (i.e., a less than the standarddosage amount) compared to subjects that are MAP3K15 reference (who mayreceive a standard dosage amount). In some embodiments, the dose of thetherapeutic agents that treat or prevent a metabolic disorder can bedecreased by about 10%, by about 20%, by about 30%, by about 40%, or byabout 50%. In addition, the subjects that are heterozygous for a MAP3K15missense variant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide can be administered less frequentlycompared to subjects that are MAP3K15 reference.

In some embodiments, the dose of the therapeutic agents that treat orprevent a metabolic disorder can be decreased by about 10%, by about20%, by about 30%, by about 40%, by about 50%, for subjects that arehomozygous for a MAP3K15 missense variant nucleic acid molecule encodinga MAP3K15 predicted loss-of-function polypeptide compared to subjectsthat are heterozygous for a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide. Insome embodiments, the dose of the therapeutic agents that treat orprevent a metabolic disorder can be decreased by about 10%, by about20%, by about 30%, by about 40%, or by about 50%. In addition, the doseof therapeutic agents that treat or prevent a metabolic disorder insubjects that are homozygous for a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide canbe administered less frequently compared to subjects that areheterozygous for a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide.

Administration of the therapeutic agents that treat or prevent ametabolic disorder and/or MAP3K15 inhibitors can be repeated, forexample, after one day, two days, three days, five days, one week, twoweeks, three weeks, one month, five weeks, six weeks, seven weeks, eightweeks, two months, or three months. The repeated administration can beat the same dose or at a different dose. The administration can berepeated once, twice, three times, four times, five times, six times,seven times, eight times, nine times, ten times, or more. For example,according to certain dosage regimens a subject can receive therapy for aprolonged period of time such as, for example, 6 months, 1 year, ormore.

Administration of the therapeutic agents that treat or prevent ametabolic disorder and/or MAP3K15 inhibitors can occur by any suitableroute including, but not limited to, parenteral, intravenous, oral,subcutaneous, intra-arterial, intracranial, intrathecal,intraperitoneal, topical, intranasal, or intramuscular. Pharmaceuticalcompositions for administration are desirably sterile and substantiallyisotonic and manufactured under GMP conditions. Pharmaceuticalcompositions can be provided in unit dosage form (i.e., the dosage for asingle administration). Pharmaceutical compositions can be formulatedusing one or more physiologically and pharmaceutically acceptablecarriers, diluents, excipients or auxiliaries. The formulation dependson the route of administration chosen. The term “pharmaceuticallyacceptable” means that the carrier, diluent, excipient, or auxiliary iscompatible with the other ingredients of the formulation and notsubstantially deleterious to the recipient thereof.

The terms “treat”, “treating”, and “treatment” and “prevent”,“preventing”, and “prevention” as used herein, refer to eliciting thedesired biological response, such as a therapeutic and prophylacticeffect, respectively. In some embodiments, a therapeutic effectcomprises one or more of a decrease/reduction in a metabolic disorder, adecrease/reduction in the severity of a metabolic disorder (such as, forexample, a reduction or inhibition of development of a metabolicdisorder), a decrease/reduction in symptoms and metabolicdisorder-related effects, delaying the onset of symptoms and metabolicdisorder-related effects, reducing the severity of symptoms of metabolicdisorder-related effects, reducing the number of symptoms and metabolicdisorder-related effects, reducing the latency of symptoms and metabolicdisorder-related effects, an amelioration of symptoms and metabolicdisorder-related effects, reducing secondary symptoms, reducingsecondary infections, preventing relapse to a metabolic disorder,decreasing the number or frequency of relapse episodes, increasinglatency between symptomatic episodes, increasing time to sustainedprogression, speeding recovery, or increasing efficacy of or decreasingresistance to alternative therapeutics, and/or an increased survivaltime of the affected host animal, following administration of the agentor composition comprising the agent. A prophylactic effect may comprisea complete or partial avoidance/inhibition or a delay of metabolicdisorder development/progression (such as, for example, a complete orpartial avoidance/inhibition or a delay), and an increased survival timeof the affected host animal, following administration of a therapeuticprotocol. Treatment of metabolic disorder, such as Type-2 diabetes,encompasses the treatment of a subject already diagnosed as having anyform of the metabolic disorder at any clinical stage or manifestation,the delay of the onset or evolution or aggravation or deterioration ofthe symptoms or signs of the metabolic disorder, and/or preventingand/or reducing the severity of the metabolic disorder. In someembodiments, the metabolic disorder is Type-2 diabetes, increasedhemoglobin A1c, or increased serum glucose.

The present disclosure also provides methods of identifying a subjecthaving an increased risk of developing a metabolic disorder. In someembodiments, the method comprises determining or having determined in abiological sample obtained from the subject the presence or absence of aMAP3K15 missense variant nucleic acid molecule (such as a genomicnucleic acid molecule, mRNA molecule, and/or cDNA molecule) encoding aMAP3K15 predicted loss-of-function polypeptide. When the subject lacks aMAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide (i.e., the subject isgenotypically categorized as a MAP3K15 reference), then the subject hasan increased risk of developing the metabolic disorder. When the subjecthas a MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide (i.e., the subject isheterozygous or homozygous for a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide),then the subject has a decreased risk of developing the metabolicdisorder.

Having a single copy of a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide is moreprotective of a subject from developing a metabolic disorder than havingno copies of a MAP3K15 missense variant nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide. Without intending to belimited to any particular theory or mechanism of action, it is believedthat a single copy of a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide (i.e.,heterozygous for a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide) is protectiveof a subject from developing a metabolic disorder, and it is alsobelieved that having two copies of a MAP3K15 missense variant nucleicacid molecule encoding a MAP3K15 predicted loss-of-function polypeptide(i.e., homozygous for a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide) may be moreprotective of a subject from developing a metabolic disorder, relativeto a subject with a single copy. Thus, in some embodiments, a singlecopy of a MAP3K15 missense variant nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide may not be completelyprotective, but instead, may be partially or incompletely protective ofa subject from developing a metabolic disorder. While not desiring to bebound by any particular theory, there may be additional factors ormolecules involved in the development of a metabolic disorder that arestill present in a subject having a single copy of a MAP3K15 missensevariant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide, thus resulting in less than completeprotection from the development of a metabolic disorder.

Determining whether a subject has a MAP3K15 missense variant nucleicacid molecule encoding a MAP3K15 predicted loss-of-function polypeptidein a biological sample from a subject and/or determining whether asubject has a MAP3K15 missense variant nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide can be carried out by anyof the methods described herein. In some embodiments, these methods canbe carried out in vitro. In some embodiments, these methods can becarried out in situ. In some embodiments, these methods can be carriedout in vivo. In any of these embodiments, the nucleic acid molecule canbe present within a cell obtained from the subject.

In some embodiments, when a subject is identified as having an increasedrisk of developing a metabolic disorder, the subject is administered atherapeutic agent that treats or prevents the metabolic disorder, and/ora MAP3K15 inhibitor, as described herein. For example, when the subjectis MAP3K15 reference, and therefore has an increased risk of developingthe metabolic disorder, the subject is administered a MAP3K15 inhibitor.In some embodiments, such a subject is also administered a therapeuticagent that treats or prevents the metabolic disorder. In someembodiments, when the subject is heterozygous for a MAP3K15 missensevariant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide, the subject is administered thetherapeutic agent that treats or prevents the metabolic disorder in adosage amount that is the same as or less than a standard dosage amount,and is also administered a MAP3K15 inhibitor. In some embodiments, sucha subject is also administered a therapeutic agent that treats orprevents the metabolic disorder. In some embodiments, when the subjectis homozygous for a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide, the subjectis administered the therapeutic agent that treats or prevents themetabolic disorder in a dosage amount that is the same as or less than astandard dosage amount. In some embodiments, the subject is MAP3K15reference. In some embodiments, the subject is heterozygous for aMAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide. In some embodiments, the subjectis homozygous for a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide.

In some embodiments, any of the methods described herein can furthercomprise determining the subject's aggregate burden of having a MAP3K15missense variant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide, and/or a MAP3K15 predictedloss-of-function variant polypeptide associated with a decreased risk ofdeveloping a metabolic disorder. The aggregate burden is the sum of allvariants in the MAP3K15 gene, which can be carried out in an associationanalysis with a metabolic disorder. In some embodiments, the subject ishomozygous for one or more MAP3K15 missense variant nucleic acidmolecules encoding a MAP3K15 predicted loss-of-function polypeptideassociated with a decreased risk of developing a metabolic disorder. Insome embodiments, the subject is heterozygous for one or more MAP3K15missense variant nucleic acid molecules encoding a MAP3K15 predictedloss-of-function polypeptide associated with a decreased risk ofdeveloping a metabolic disorder. The result of the association analysissuggests that MAP3K15 missense variant nucleic acid molecules encodingMAP3K15 predicted loss-of-function polypeptides are associated withdecreased risk of developing a metabolic disorder. When the subject hasa lower aggregate burden, the subject is at a higher risk of developingthe metabolic disorder and the subject is administered or continued tobe administered the therapeutic agent that treats or prevents themetabolic disorder in a standard dosage amount, and/or a MAP3K15inhibitor. When the subject has a greater aggregate burden, the subjectis at a lower risk of developing the metabolic disorder and the subjectis administered or continued to be administered the therapeutic agentthat treats or prevents the metabolic disorder in an amount that is thesame as or less than the standard dosage amount. The greater theaggregate burden, the lower the risk of developing the metabolicdisorder.

MAP3K15 variants that can be used in the aggregate burden analysisinclude any one or more, or any combination, of the following:

Variant rsID Transcript IDs 23:19360753:G:C ENST0000033888323:19360753:G:T ENST00000338883 23:19360754:C:G ENST0000033888323:19360754:C:T ENST00000338883 23:19360754:C:A ENST0000033888323:19360757:T:C ENST00000338883 23:19360758:G:GTC ENST0000033888323:19360758:G:T ENST00000338883 23:19360758:G:GTCTT rs1199427438ENST00000338883 23:19360758:G:C rs758692867 ENST0000033888323:19360759:T:G ENST00000338883 23:19360760:CTT:C ENST0000033888323:19360760:C:CTT rs762409221 ENST00000338883 23:19360763:T:CENST00000338883 23:19360765:G:GT ENST00000338883 23:19360765:G:TENST00000338883 23:19360766:T:TTTCTGAGGCC ENST0000033888323:19360768:T:G rs1407334158 ENST00000338883 23:19360770:TG:Trs1165543621 ENST00000338883 23:19360771:G:A ENST0000033888323:19360772:A:G rs1434269786 ENST00000338883 23:19360774:G:AENST00000338883 23:19360775:C:A ENST00000338883 23:19360778:C:TENST00000338883 23:19360781:G:C ENST00000338883 23:19360783:G:TENST00000338883 23:19360785:C:A ENST00000338883 23:19360785:C:Grs145675672 ENST00000338883 23:19360786:CT:C ENST0000033888323:19360786:C:T rs61744590 ENST00000338883 23:19360790:T:CENST00000338883 23:19360793:A:T ENST00000338883 23:19360795:T:Crs778346850 ENST00000338883 23:19360804:G:T ENST0000033888323:19360804:G:A rs756039907 ENST00000338883 23:19360805:C:T rs147753175ENST00000338883 23:19360806:A:T ENST00000338883 23:19360807:C:AENST00000338883 23:19360809:C:T ENST00000338883 23:19360810:C:Trs766954168 ENST00000338883 23:19360811:A:AGAGT ENST0000033888323:19360814:G:A rs1404016169 ENST00000338883 23:19360816:C:Grs1270522443 ENST00000338883 23:19360819:CA:C rs761048720ENST00000338883 23:19360819:C:T rs747270244 ENST0000033888323:19360820:A:T ENST00000338883 23:19360823:G:T ENST0000033888323:19360831:C:T ENST00000338883 23:19360831:C:G ENST0000033888323:19361336:T:TA rs1184403880 ENST00000338883 23:19361338:C:Grs377382652 ENST00000338883 23:19361338:C:T rs377382652 ENST0000033888323:19361339:C:G ENST00000338883 23:19361339:C:A rs753516995ENST00000338883 23:19361339:C:T rs753516995 ENST0000033888323:19361340:G:A rs748198804 ENST00000338883 23:19361341:TA:T rs762188631ENST00000338883 23:19361345:C:A ENST00000338883 23:19361345:C:TENST00000338883 23:19361345:C:G ENST00000338883 23:19361346:G:Ars148399187 ENST00000338883 23:19361346:GA:G ENST0000033888323:19361349:G:T ENST00000338883 23:19361349:G:A rs1448313019ENST00000338883 23:19361350:G:T rs763409232 ENST0000033888323:19361354:C:T rs977795204 ENST00000338883 23:19361357:A:G rs142533585ENST00000338883 23:19361358:G:T ENST00000338883 23:19361359:A:Crs1371710222 ENST00000338883 23:19361361:C:A ENST0000033888323:19361362:T:G ENST00000338883 23:19361364:C:G ENST0000033888323:19361367:T:G ENST00000338883 23:19361369:G:A rs774659644ENST00000338883 23:19361370:T:G rs150957359 ENST0000033888323:19361370:T:C ENST00000338883 23:19361376:CAT:C ENST0000033888323:19361388:C:A rs750874490 ENST00000338883 23:19361390:G:A rs1274425240ENST00000338883 23:19361390:GA:G ENST00000338883 23:19361390:G:CENST00000338883 23:19361391:A:T ENST00000338883 23:19361394:G:AENST00000338883 23:19361394:G:C rs1207639901 ENST0000033888323:19361396:G:A ENST00000338883 23:19361399:TA:T ENST0000033888323:19361402:C:A ENST00000338883 23:19361403:C:T rs144734730ENST00000338883 23:19361404:CT:C rs751563348 ENST0000033888323:19361408:T:C ENST00000338883 23:19361416:C:G ENST0000033888323:19361416:C:T rs780260798 ENST00000338883 23:19361416:C:A rs780260798ENST00000338883 23:19361491:A:G ENST00000338883 23:19361492:C:TENST00000338883 23:19361493:CT:C ENST00000338883 23:19361493:C:Grs781517592 ENST00000338883 23:19361494:T:A rs989329615 ENST0000033888323:19361495:T:C ENST00000338883 23:19361497:T:A ENST0000033888323:19361498:C:T ENST00000338883 23:19361500:A:G rs759883184ENST00000338883 23:19361501:T:C rs1269336518 ENST0000033888323:19361503:G:C ENST00000338883 23:19361503:G:A ENST0000033888323:19361505:C:G ENST00000338883 23:19361505:CTT:C ENST0000033888323:19361509:G:C ENST00000338883 23:19361511:A:T ENST0000033888323:19361511:A:C rs772494786 ENST00000338883 23:19361516:C:TENST00000338883 23:19361519:C:T rs1490120645 ENST0000033888323:19361522:G:A ENST00000338883 23:19361522:G:C rs15943 ENST0000033888323:19361527:C:T rs760297711 ENST00000338883 23:19361527:C:GENST00000338883 23:19361528:G:A rs763826263 ENST0000033888323:19361530:A:C ENST00000338883 23:19361533:C:T ENST0000033888323:19361534:A:T ENST00000338883 23:19361536:T:A ENST0000033888323:19361536:TCTATAAG:T ENST00000338883 23:19361537:CTA:C ENST0000033888323:19361539:A:C ENST00000338883 23:19361539:A:G ENST0000033888323:19361543:G:T ENST00000338883 23:19361545:T:C ENST0000033888323:19361546:C:CT ENST00000338883 23:19361546:C:G rs1350886167ENST00000338883 23:19361546:CTT:C ENST00000338883 23:19361548:T:Crs753243729 ENST00000338883 23:19361549:T:C ENST0000033888323:19361551:T:G ENST00000338883 23:19361552:C:T rs761409953ENST00000338883 23:19361554:G:C ENST00000338883 23:19361554:G:AENST00000338883 23:19361556:T:A ENST00000338883 23:19361557:C:TENST00000338883 23:19361561:G:A ENST00000338883 23:19361564:C:Ars368526609 ENST00000338883 23:19361564:C:T rs368526609 ENST0000033888323:19361565:GT:G ENST00000338883 23:19361565:G:T rs372102191ENST00000338883 23:19361566:T:G ENST00000338883 23:19361567:A:CENST00000338883 23:19361569:G:C rs140380348 ENST0000033888323:19361570:G:C ENST00000338883 23:19361572:C:T ENST0000033888323:19361575:G:A ENST00000338883 23:19361576:C:T ENST0000033888323:19361577:TG:T ENST00000338883 23:19361579:G:C rs778062708ENST00000338883 23:19361580:G:T ENST00000338883 23:19361583:C:Grs749306111 ENST00000338883 23:19361585:CTG:C ENST0000033888323:19361585:C:T ENST00000338883 23:19361587:G:T ENST0000033888323:19361587:G:A ENST00000338883 23:19361587:G:C rs1296783815ENST00000338883 23:19361588:TA:T ENST00000338883 23:19361591:T:TArs1385917519 ENST00000338883 23:19361592:A:AC ENST0000033888323:19361593:C:T ENST00000338883 23:19362736:AC:A ENST0000033888323:19362736:A:G ENST00000338883 23:19362736:A:T ENST0000033888323:19362737:C:T ENST00000338883 23:19362743:G:A rs952016428ENST00000338883 23:19362743:G:T ENST00000338883 23:19362743:G:CENST00000338883 23:19362744:AT:A ENST00000338883 23:19362744:A:TENST00000338883 23:19362744:A:G ENST00000338883 23:19362748:TA:TENST00000338883 23:19362749:A:G ENST00000338883 23:19362749:A:TENST00000338883 23:19362752:T:G rs1277278348 ENST0000033888323:19362754:T:A ENST00000338883 23:19362758:T:C rs754813662ENST00000338883 23:19362759:G:T ENST00000338883 23:19362759:GA:GENST00000338883 23:19362762:G:T ENST00000338883 23:19362762:G:Ars764208000 ENST00000338883 23:19362763:G:T rs149055708 ENST0000033888323:19362764:T:C ENST00000338883 23:19362765:G:T ENST0000033888323:19362767:T:C ENST00000338883 23:19362769:C:G rs201314812ENST00000338883 23:19362772:T:A ENST00000338883 23:19362773:T:GENST00000338883 23:19362779:G:A ENST00000338883 23:19362779:G:TENST00000338883 23:19362786:G:T ENST00000338883 23:19362786:G:Ars745964693 ENST00000338883 23:19362787:TTC:T ENST0000033888323:19362789:C:T ENST00000338883 23:19362789:C:A rs758795249ENST00000338883 23:19362792:G:C rs1161578178 ENST0000033888323:19362796:T:A ENST00000338883 23:19362798:G:T ENST0000033888323:19362800:C:T rs372854064 ENST00000338883 23:19362801:G:A rs774477994ENST00000338883 23:19362803:A:T ENST00000338883 23:19362803:A:GENST00000338883 23:19362806:A:G ENST00000338883 23:19362807:G:Crs747281853 ENST00000338883 23:19362808:AT:A ENST0000033888323:19362809:T:C rs1364371261 ENST00000338883 23:19362810:T:Crs1315221917 ENST00000338883 23:19362811:C:G rs769125014 ENST0000033888323:19362812:TG:T ENST00000338883 23:19362813:G:T ENST0000033888323:19362814:G:T ENST00000338883 23:19362814:G:C rs145535604ENST00000338883 23:19362814:GT:G ENST00000338883 23:19362816:ACTCT:Ars774006713 ENST00000338883 23:19362816:ACT:A rs1491461563ENST00000338883 23:19362816:A:ACT rs747607452 ENST0000033888323:19362818:T:C ENST00000338883 23:19362818:T:A rs747844024ENST00000338883 23:19362818:T:G ENST00000338883 23:19362819:C:TENST00000338883 23:19362820:T:G ENST00000338883 23:19362821:C:AENST00000338883 23:19362821:C:G ENST00000338883 23:19362823:CTCTT:Crs760983657 ENST00000338883 23:19362824:T:A ENST0000033888323:19362825:CT:C rs1231757389 ENST00000338883 23:19362825:C:TENST00000338883 23:19362834:CT:C ENST00000338883 23:19362834:C:TENST00000338883 23:19362836:AG:A ENST00000338883 23:19362836:A:TENST00000338883 23:19362837:G:T ENST00000338883 23:19362837:G:Crs772800110 ENST00000338883 23:19362839:T:G ENST0000033888323:19362840:G:T ENST00000338883 23:19362840:GT:G ENST0000033888323:19362842:TC:T ENST00000338883 23:19362844:C:A rs1281522700ENST00000338883 23:19362844:CA:C rs868296960 ENST0000033888323:19362849:G:T ENST00000338883 23:19362849:G:A rs762556289ENST00000338883 23:19362851:C:T rs1230820520 ENST0000033888323:19369053:C:A ENST00000338883 23:19369053:C:T rs1436613793ENST00000338883 23:19369055:T:A ENST00000338883 23:19369067:G:AENST00000338883 23:19369067:G:T ENST00000338883 23:19369069:C:TENST00000338883 23:19369070:T:C rs894813705 ENST0000033888323:19369070:T:A ENST00000338883 23:19369073:G:A rs780414578ENST00000338883 23:19369076:C:T rs747620273 ENST0000033888323:19369079:C:T ENST00000338883 23:19369081:A:G ENST0000033888323:19369083:C:G ENST00000338883 23:19369085:G:A rs1449183471ENST00000338883 23:19369090:C:T ENST00000338883 23:19369093:A:CENST00000338883 23:19369095:G:C ENST00000338883 23:19369098:C:CTENST00000338883 23:19369100:G:A ENST00000338883 23:19369101:C:GENST00000338883 23:19369102:T:C ENST00000338883 23:19369104:G:CENST00000338883 23:19369106:G:A rs1164149506 ENST0000033888323:19369109:G:A rs769504223 ENST00000338883 23:19369111:T:C rs763685191ENST00000338883 23:19369114:G:C ENST00000338883 23:19369115:C:Grs748733061 ENST00000338883 23:19369115:C:A ENST0000033888323:19369116:C:A ENST00000338883 23:19369116:C:CTCCT ENST0000033888323:19369118:C:T ENST00000338883 23:19369120:T:C rs770538660ENST00000338883 23:19369124:C:T rs369366467 ENST0000033888323:19369126:G:A rs759563426 ENST00000338883 23:19369127:G:AENST00000338883 23:19369128:TC:T ENST00000338883 23:19369129:C:TENST00000338883 23:19369130:C:A ENST00000338883 23:19369130:C:Trs771921808 ENST00000338883 23:19369132:G:C ENST0000033888323:19369138:G:A ENST00000338883 23:19369139:G:A rs1331944995ENST00000338883 23:19369141:G:A ENST00000338883 23:19369141:G:CENST00000338883 23:19369142:G:A rs1193093159 ENST0000033888323:19369147:C:A rs1215035447 ENST00000338883 23:19369154:C:T rs760471862ENST00000338883 23:19369156:G:A rs201603186 ENST0000033888323:19369156:G:C ENST00000338883 23:19369156:G:T ENST0000033888323:19369157:C:T ENST00000338883 23:19369160:C:T rs988090325ENST00000338883 23:19369170:CT:C ENST00000338883 23:19369171:T:Grs370097132 ENST00000338883 23:19369171:T:C rs370097132 ENST0000033888323:19369172:T:C rs138105109 ENST00000338883 23:19369177:A:GENST00000338883 23:19369180:C:A ENST00000338883 23:19369182:T:AENST00000338883 23:19369182:T:TG ENST00000338883 23:19369184:C:TENST00000338883 23:19369195:G:A ENST00000338883 23:19369195:G:TENST00000338883 23:19369196:T:A ENST00000338883 23:19369198:G:TENST00000338883 23:19369198:G:A rs1165786720 ENST0000033888323:19369199:G:T ENST00000338883 23:19369200:C:A rs1395086883ENST00000338883 23:19369201:T:C ENST00000338883 23:19369202:C:GENST00000338883 23:19369206:G:C ENST00000338883 23:19369211:C:AENST00000338883 23:19369213:C:T rs377027094 ENST0000033888323:19369214:G:A rs148312150 ENST00000338883 23:19369214:G:A rs148312150ENST00000338883 23:19369216:A:G rs1453534435 ENST0000033888323:19369217:G:A rs756604026 ENST00000338883 23:19369218:C:G rs777561813ENST00000338883 23:19369219:T:A rs1329058417 ENST0000033888323:19370957:A:G ENST00000338883 23:19370960:TG:T ENST0000033888323:19370961:G:T ENST00000338883 23:19370965:T:A ENST0000033888323:19370965:T:C ENST00000338883 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23:19488937:G:AENST00000338883 23:19488944:C:CG ENST00000338883 23:19488944:C:Ars1432285061 ENST00000338883 23:19488944:C:T ENST0000033888323:19488945:G:C ENST00000338883 23:19488945:G:T ENST0000033888323:19488946:C:T rs911879562 ENST00000338883 23:19488947:T:CENST00000338883 23:19488948:C:T rs1378891430 ENST0000033888323:19488949:A:G ENST00000338883 23:19488949:A:T rs1324637533ENST00000338883 23:19488950:T:C ENST00000338883 23:19488952:T:CENST00000338883 23:19488955:AC:A ENST00000338883 23:19488959:C:TENST00000338883 23:19488961:GCA:G ENST00000338883 23:19488961:G:AENST00000338883 23:19488967:T:C ENST00000338883 23:19488968:C:GENST00000338883 23:19514899:A:T ENST00000338883 23:19514903:G:CENST00000338883 23:19514903:G:A rs1171701407 ENST0000033888323:19514903:G:T ENST00000338883 23:19514904:C:T ENST0000033888323:19514904:C:A rs768115068 ENST00000338883 23:19514905:G:CENST00000338883 23:19514905:G:T ENST00000338883 23:19514907:C:Trs1456668678 ENST00000338883 23:19514908:G:T ENST0000033888323:19514909:T:TA ENST00000338883 23:19514911:GA:G ENST0000033888323:19514915:G:A rs1395412359 ENST00000338883 23:19514915:G:TENST00000338883 23:19514916:C:T ENST00000338883 23:19514919:C:TENST00000338883 23:19514922:G:T ENST00000338883 23:19514924:A:TENST00000338883 23:19514925:C:T ENST00000338883 23:19514925:C:AENST00000338883 23:19514927:G:A ENST00000338883 23:19514927:G:TENST00000338883 23:19514930:G:A ENST00000338883 23:19514931:TC:TENST00000338883 23:19514932:CT:C ENST00000338883 23:19514933:T:AENST00000338883 23:19514934:C:A rs866314004 ENST0000033888323:19514936:C:A ENST00000338883 23:19514936:C:T ENST0000033888323:19514937:C:A rs1468690195 ENST00000338883 23:19514940:A:TENST00000338883 23:19514943:C:T ENST00000338883 23:19514946:G:TENST00000338883 23:19514948:TC:T ENST00000338883 23:19514949:C:Grs1363169158 ENST00000338883 23:19514951:C:T ENST0000033888323:19514952:C:T ENST00000338883 23:19514952:C:G ENST0000033888323:19514953:G:T ENST00000338883 23:19514957:G:A ENST0000033888323:19514958:G:A ENST00000338883 23:19514961:C:A ENST0000033888323:19514961:C:T rs1486540523 ENST00000338883 23:19514964:A:GENST00000338883 23:19514964:A:T ENST00000338883 23:19514966:G:Ars1253605138 ENST00000338883 23:19514969:A:G ENST0000033888323:19514970:G:C rs753477495 ENST00000338883 23:19514973:G:AENST00000338883 23:19514975:G:C ENST00000338883 23:19514976:C:Grs757004787 ENST00000338883 23:19514978:C:T rs866103370 ENST0000033888323:19514982:C:T rs1054465189 ENST00000338883 23:19514984:G:AENST00000338883 23:19514985:C:A ENST00000338883 23:19514986:C:GENST00000338883 23:19514986:C:A ENST00000338883 23:19514988:C:Trs758239336 ENST00000338883 23:19514990:C:G rs895374109 ENST0000033888323:19514991:A:C ENST00000338883 23:19514993:G:C ENST0000033888323:19514993:G:A rs780108276 ENST00000338883 23:19514994:C:TENST00000338883 23:19514996:C:A rs1378428802 ENST0000033888323:19514996:C:G ENST00000338883 23:19514996:C:T ENST0000033888323:19514997:G:A ENST00000338883 23:19514997:G:C ENST0000033888323:19515002:AG:A rs1394200836 ENST00000338883 23:19515003:G:TENST00000338883 23:19515009:G:A rs1335205066 ENST0000033888323:19515011:C:G rs754707908 ENST00000338883 23:19515011:C:TENST00000338883 23:19515014:G:T ENST00000338883 23:19515014:GC:GENST00000338883 23:19515015:C:T ENST00000338883 23:19515018:C:TENST00000338883 23:19515019:AGCCTCCGG:A rs1261324909 ENST0000033888323:19515020:G:T ENST00000338883 23:19515026:G:C rs780969640ENST00000338883 23:19515026:G:T ENST00000338883 23:19515026:G:Ars780969640 ENST00000338883 23:19515027:G:T ENST0000033888323:19515028:GC:G rs759538376 ENST00000338883 23:19515029:C:TENST00000338883 23:19515030:C:A ENST00000338883 23:19515032:C:GENST00000338883 23:19515033:C:CG ENST00000338883 23:19515035:G:TENST00000338883 23:19515036:C:T ENST00000338883 23:19515038:G:Crs749471068 ENST00000338883 23:19515038:G:T ENST0000033888323:19515038:G:A ENST00000338883 23:19515039:C:T rs1361659149ENST00000338883 23:19515041:C:T ENST00000338883 23:19515042:C:TENST00000338883 23:19515044:C:T ENST00000338883 23:19515045:C:TENST00000338883 23:19515045:C:A rs1258691915 ENST0000033888323:19515045:C:G ENST00000338883 23:19515047:T:C ENST0000033888323:19515047:T:A ENST00000338883 23:19515048:G:T ENST0000033888323:19515050:G:C ENST00000338883 23:19515050:G:T ENST0000033888323:19515051:A:T ENST00000338883 23:19515052:G:GCT ENST0000033888323:19515052:G:T ENST00000338883 23:19515052:GCT:G ENST0000033888323:19515053:C:T rs1472440446 ENST00000338883 23:19515054:T:CENST00000338883 23:19515055:C:A ENST00000338883 23:19515056:T:GENST00000338883 23:19515056:T:A ENST0000033888323:19515057:C:CACTGCGCACGTAT ENST00000338883 23:19515057:C:Trs1025499625 ENST00000338883 23:19515059:C:G ENST0000033888323:19515059:C:T rs1401496726 ENST00000338883 23:19515060:T:CENST00000338883 23:19515062:C:T rs1175519940 ENST0000033888323:19515062:C:A ENST00000338883 23:19515063:G:A ENST0000033888323:19515063:G:T rs1357476322 ENST00000338883 23:19515065:A:Trs1464521740 ENST00000338883 23:19515065:A:G rs1464521740ENST00000338883 23:19515066:C:A ENST00000338883 23:19515066:C:Trs1426565124 ENST00000338883 23:19515067:GTA:G ENST0000033888323:19515067:G:T ENST00000338883 23:19515071:A:G ENST0000033888323:19515072:C:G ENST00000338883 23:19515072:C:A ENST0000033888323:19515072:C:T ENST00000338883 23:19515074:GC:G ENST0000033888323:19515074:G:A ENST00000338883 23:19515074:G:T rs1314606733ENST00000338883 23:19515075:C:T ENST00000338883 23:19515077:C:Trs952671859 ENST00000338883 23:19515078:G:A ENST0000033888323:19515083:G:T ENST00000338883 23:19515083:G:A ENST0000033888323:19515084:C:T ENST00000338883 23:19515084:C:A ENST0000033888323:19515084:C:G ENST00000338883 23:19515086:C:T ENST0000033888323:19515087:G:A ENST00000338883 23:19515089:C:A ENST0000033888323:19515089:C:T ENST00000338883 23:19515090:G:A ENST0000033888323:19515092:G:A ENST00000338883 23:19515092:G:T ENST0000033888323:19515093:G:T ENST00000338883 23:19515093:G:A rs911136448ENST00000338883 23:19515095:C:T ENST00000338883 23:19515096:C:AENST00000338883 23:19515096:C:T ENST00000338883 23:19515097:GC:GENST00000338883 23:19515098:C:T ENST00000338883 23:19515098:C:GENST00000338883 23:19515099:C:T ENST00000338883 23:19515102:C:Ars1223982658 ENST00000338883 23:19515102:C:CA ENST0000033888323:19515102:C:G rs1223982658 ENST00000338883 23:19515102:C:TENST00000338883 23:19515103:ACT:A ENST00000338883 23:19515103:A:TENST00000338883 23:19515104:C:T ENST00000338883 23:19515106:C:AENST00000338883 23:19515107:T:G ENST00000338883 23:19515108:C:TENST00000338883 23:19515108:C:G ENST00000338883 23:19515110:C:TENST00000338883 23:19515110:C:G ENST00000338883 23:19515112:C:AENST00000338883 23:19515114:CGCCGCTGCCGCCT:C ENST0000033888323:19515114:C:A ENST00000338883 23:19515114:C:T ENST0000033888323:19515116:C:T ENST00000338883 23:19515117:C:A ENST0000033888323:19515117:C:T ENST00000338883 23:19515118:G:GCTGCCGC ENST0000033888323:19515118:GCTGCCGC:G ENST00000338883 23:19515118:G:T ENST0000033888323:19515119:C:T ENST00000338883 23:19515120:T:G ENST0000033888323:19515122:C:T ENST00000338883 23:19515122:C:G rs1414337775ENST00000338883 23:19515123:C:T ENST00000338883 23:19515125:C:AENST00000338883 23:19515126:C:G ENST00000338883 23:19515126:C:TENST00000338883 23:19515127:TG:T ENST00000338883 23:19515128:G:AENST00000338883 23:19515128:G:T ENST00000338883 23:19515129:C:TENST00000338883 23:19515129:C:A ENST00000338883 23:19515131:G:TENST00000338883 23:19515131:G:A ENST00000338883 23:19515132:C:TENST00000338883 23:19515134:C:T rs771203031 ENST0000033888323:19515134:C:A ENST00000338883 23:19515135:C:T ENST0000033888323:19515135:C:G ENST00000338883 23:19515137:T:G ENST0000033888323:19515138:C:T ENST00000338883 23:19515140:G:T ENST0000033888323:19515141:C:T ENST00000338883 23:19515143:G:A rs1281598957ENST00000338883 23:19515143:G:T ENST00000338883 23:19515143:GC:GENST00000338883 23:19515147:C:G ENST00000338883 23:19515147:C:AENST00000338883 23:19515147:C:T ENST00000338883 23:19515148:G:TENST00000338883 23:19515149:T:G ENST00000338883 23:19515150:C:AENST00000338883 23:19515150:C:T rs976452422 ENST0000033888323:19515152:G:A ENST00000338883 23:19515152:G:T ENST0000033888323:19515153:G:T ENST00000338883 23:19515155:TC:T ENST0000033888323:19515155:T:TC ENST00000338883 23:19515155:T:C ENST0000033888323:19515155:T:G ENST00000338883 23:19515158:G:T ENST0000033888323:19515158:G:A ENST00000338883 23:19515159:C:T ENST0000033888323:19515161:G:T ENST00000338883 23:19515162:G:T ENST0000033888323:19515162:GCCCGGCCGCGCCCTCCACC:G rs1299580669 ENST0000033888323:19515165:C:T ENST00000338883 23:19515165:C:G ENST0000033888323:19515167:G:A rs1460143738 ENST00000338883 23:19515168:C:TENST00000338883 23:19515170:G:A ENST00000338883 23:19515170:G:CENST00000338883 23:19515170:G:T rs1369796869 ENST0000033888323:19515171:C:T ENST00000338883 23:19515171:C:A ENST0000033888323:19515173:C:A ENST00000338883 23:19515173:C:T ENST0000033888323:19515174:C:T ENST00000338883 23:19515175:C:G ENST0000033888323:19515176:TCC:T ENST00000338883 23:19515177:C:G ENST0000033888323:19515179:AC:A ENST00000338883 23:19515179:A:G ENST0000033888323:19515180:C:T ENST00000338883 23:19515180:C:CCG ENST0000033888323:19515182:C:G ENST00000338883 23:19515183:C:A ENST0000033888323:19515183:C:T ENST00000338883 23:19515185:G:A rs1426255554ENST00000338883 23:19515185:G:C ENST00000338883 23:19515186:G:CENST00000338883 23:19515188:G:A rs1234945987 ENST0000033888323:19515189:G:A ENST00000338883 23:19515191:G:A rs1448815279ENST00000338883 23:19515191:G:T ENST00000338883 23:19515191:G:CENST00000338883 23:19515194:G:T ENST00000338883 23:19515194:G:AENST00000338883 23:19515195:G:A ENST00000338883 23:19515196:G:TENST00000338883 23:19515197:C:A ENST00000338883 23:19515197:C:TENST00000338883 23:19515198:A:C ENST00000338883 23:19515198:ACT:AENST00000338883 23:19515198:A:G ENST00000338883 23:19515203:G:CENST00000338883 23:19515204:G:A rs1284762730 ENST0000033888323:19515206:G:T ENST00000338883 23:19515209:T:A ENST0000033888323:19515210:C:A ENST00000338883 23:19515211:G:T ENST0000033888323:19515213:TCG:T ENST00000338883 23:19515215:GC:G ENST0000033888323:19515215:G:A ENST00000338883 23:19515215:G:T ENST0000033888323:19515216:C:G ENST00000338883 23:19515216:C:T rs1482854182ENST00000338883 23:19515216:CCG:C ENST00000338883 23:19515218:G:AENST00000338883 23:19515218:G:T ENST00000338883 23:19515218:GC:GENST00000338883 23:19515221:C:A ENST00000338883 23:19515222:C:GENST00000338883 23:19515225:G:A ENST00000338883 23:19515227:G:AENST00000338883 23:19515227:G:C ENST00000338883 23:19515227:G:TENST00000338883 23:19515231:C:T ENST00000338883 23:19515231:C:GENST00000338883 23:19515233:G:T ENST00000338883 23:19515234:C:Trs1225209367 ENST00000338883 23:19515240:C:G ENST0000033888323:19515243:T:A ENST00000338883 23:19515246:C:T rs1041842228ENST00000338883 23:19515248:C:T rs1265407890 ENST0000033888323:19515249:C:T rs1225904878 ENST00000338883 23:19515251:C:GENST00000338883 23:19515252:C:G rs1335896137 ENST0000033888323:19515252:C:T ENST00000338883 23:19515253:G:T ENST0000033888323:19515253:G:C ENST00000338883 23:19515255:T:C ENST0000033888323:19515256:C:G ENST00000338883 23:19515257:T:C ENST0000033888323:19515260:A:C ENST00000338883 23:19515260:A:G rs1276433816ENST00000338883 23:19515261:T:C ENST00000338883

In some embodiments, the subject's aggregate burden of having any one ormore MAP3K15 missense variant nucleic acid molecules encoding a MAP3K15predicted loss-of-function polypeptide represents a weighted sum of aplurality of any of the MAP3K15 missense variant nucleic acid moleculesencoding MAP3K15 predicted loss-of-function polypeptides. In someembodiments, the aggregate burden is calculated using at least about 2,at least about 3, at least about 4, at least about 5, at least about 10,at least about 20, at least about 30, at least about 40, at least about50, at least about 60, at least about 70, at least about 80, at leastabout 100, at least about 120, at least about 150, at least about 200,at least about 250, at least about 300, at least about 400, at leastabout 500, at least about 1,000, at least about 10,000, at least about100,000, or at least about or more than 1,000,000 genetic variantspresent in or around (up to 10 Mb) the MAP3K15 gene where the geneticburden is the number of alleles multiplied by the association estimatewith metabolic disorder or related outcome for each allele (e.g., aweighted polygenic burden score). This can include any genetic variants,regardless of their genomic annotation, in proximity to the MAP3K15 gene(up to 10 Mb around the gene) that show a non-zero association withmetabolic disorder-related traits in a genetic association analysis. Insome embodiments, when the subject has an aggregate burden above adesired threshold score, the subject has a decreased risk of developinga metabolic disorder. In some embodiments, when the subject has anaggregate burden below a desired threshold score, the subject has anincreased risk of developing a metabolic disorder.

In some embodiments, the aggregate burden may be divided into quintiles,e.g., top quintile, intermediate quintile, and bottom quintile, whereinthe top quintile of aggregate burden corresponds to the lowest riskgroup and the bottom quintile of aggregate burden corresponds to thehighest risk group. In some embodiments, a subject having a greateraggregate burden comprises the highest weighted aggregate burdens,including, but not limited to the top 10%, top 20%, top 30%, top 40%, ortop 50% of aggregate burdens from a subject population. In someembodiments, the genetic variants comprise the genetic variants havingassociation with metabolic disorder in the top 10%, top 20%, top 30%,top 40%, or top 50% of p-value range for the association. In someembodiments, each of the identified genetic variants comprise thegenetic variants having association with a metabolic disorder withp-value of no more than about 10⁻², about 10⁻³, about 10⁻⁴, about 10⁻⁵,about 10⁻⁶, about 10⁻⁷, about 10⁻⁸, about 10⁻⁹, about 10⁻¹⁰, about10⁻¹¹, about 10⁻¹², about 10⁻¹³, about 10⁻¹⁴, about or 10⁻¹⁵. In someembodiments, the identified genetic variants comprise the geneticvariants having association with a metabolic disorder with a p-value ofless than 5×10⁻⁸. In some embodiments, the identified genetic variantscomprise genetic variants having association with a metabolic disorderin high-risk subjects as compared to the rest of the referencepopulation with odds ratio (OR) about 1.5 or greater, about 1.75 orgreater, about 2.0 or greater, or about 2.25 or greater for the top 20%of the distribution; or about 1.5 or greater, about 1.75 or greater,about 2.0 or greater, about 2.25 or greater, about 2.5 or greater, orabout 2.75 or greater. In some embodiments, the odds ratio (OR) mayrange from about 1.0 to about 1.5, from about 1.5 to about 2.0, fromabout 2.0 to about 2.5, from about 2.5 to about 3.0, from about 3.0 toabout 3.5, from about 3.5 to about 4.0, from about 4.0 to about 4.5,from about 4.5 to about 5.0, from about 5.0 to about 5.5, from about 5.5to about 6.0, from about 6.0 to about 6.5, from about 6.5 to about 7.0,or greater than 7.0. In some embodiments, high-risk subjects comprisesubjects having aggregate burdens in the bottom decile, quintile, ortertile in a reference population. The threshold of the aggregate burdenis determined on the basis of the nature of the intended practicalapplication and the risk difference that would be considered meaningfulfor that practical application.

In some embodiments, when a subject is identified as having an increasedrisk of developing a metabolic disorder, the subject is furtheradministered a therapeutic agent that treats or prevents the metabolicdisorder, and/or a MAP3K15 inhibitor, as described herein. For example,when the subject is MAP3K15 reference, and therefore has an increasedrisk of developing a metabolic disorder, the subject is administered aMAP3K15 inhibitor. In some embodiments, such a subject is alsoadministered a therapeutic agent that treats or prevents the metabolicdisorder. In some embodiments, when the subject is heterozygous for aMAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide, the subject is administered thetherapeutic agent that treats or prevents the metabolic disorder in adosage amount that is the same as or less than a standard dosage amount,and is also administered a MAP3K15 inhibitor. In some embodiments, thesubject is MAP3K15 reference. In some embodiments, the subject isheterozygous for a MAP3K15 missense variant nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide. Furthermore,when the subject has a lower aggregate burden for having a MAP3K15missense variant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide, and therefore has an increased risk ofdeveloping a metabolic disorder, the subject is administered atherapeutic agent that treats or prevents the metabolic disorder. Insome embodiments, when the subject has a lower aggregate burden forhaving a MAP3K15 missense variant nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide, the subject isadministered the therapeutic agent that treats or prevents a metabolicdisorder in a dosage amount that is the same as or greater than thestandard dosage amount administered to a subject who has a greateraggregate burden for having a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide.

The present disclosure also provides methods of detecting the presenceor absence of a MAP3K15 missense variant nucleic acid molecule (i.e., agenomic nucleic acid molecule, an mRNA molecule, or a cDNA moleculeproduced from an mRNA molecule) encoding a MAP3K15 predictedloss-of-function polypeptide in a biological sample from a subject. Itis understood that gene sequences within a population and mRNA moleculesencoded by such genes can vary due to polymorphisms such assingle-nucleotide polymorphisms. The sequences provided herein for theMAP3K15 variant genomic nucleic acid molecule, MAP3K15 variant mRNAmolecule, and MAP3K15 variant cDNA molecule are only exemplarysequences. Other sequences for the MAP3K15 variant genomic nucleic acidmolecule, variant mRNA molecule, and variant cDNA molecule are alsopossible.

The biological sample can be derived from any cell, tissue, orbiological fluid from the subject. The biological sample may compriseany clinically relevant tissue, such as a bone marrow sample, a tumorbiopsy, a fine needle aspirate, or a sample of bodily fluid, such asblood, gingival crevicular fluid, plasma, serum, lymph, ascitic fluid,cystic fluid, or urine. In some cases, the sample comprises a buccalswab. The biological sample used in the methods disclosed herein canvary based on the assay format, nature of the detection method, and thetissues, cells, or extracts that are used as the sample. A biologicalsample can be processed differently depending on the assay beingemployed. For example, when detecting any MAP3K15 missense variantnucleic acid molecule encoding any MAP3K15 predicted loss-of-functionpolypeptide, preliminary processing designed to isolate or enrich thebiological sample for the genomic DNA can be employed. A variety oftechniques may be used for this purpose. When detecting the level of anyMAP3K15 variant mRNA molecule, different techniques can be used enrichthe biological sample with mRNA molecules. Various methods to detect thepresence or level of an mRNA molecule or the presence of a particularvariant genomic DNA locus can be used.

In some embodiments, detecting a MAP3K15 missense variant nucleic acidmolecule encoding a MAP3K15 predicted loss-of-function polypeptide in asubject comprises performing a sequence analysis on a biological sampleobtained from the subject to determine whether a MAP3K15 genomic nucleicacid molecule in the biological sample, and/or a MAP3K15 mRNA moleculein the biological sample, and/or a MAP3K15 cDNA molecule produced froman mRNA molecule in the biological sample, comprises one or morevariations that cause a loss-of-function (partial or complete) or arepredicted to cause a loss-of-function (partial or complete).

In some embodiments, the methods of detecting the presence or absence ofa MAP3K15 missense variant nucleic acid molecule encoding a MAP3K15predicted loss-of-function polypeptide (such as, for example, a genomicnucleic acid molecule, an mRNA molecule, and/or a cDNA molecule producedfrom an mRNA molecule) in a subject, comprise performing an assay on abiological sample obtained from the subject. The assay determineswhether a nucleic acid molecule in the biological sample comprises aparticular nucleotide sequence.

In some embodiments, the biological sample comprises a cell or celllysate. Such methods can further comprise, for example, obtaining abiological sample from the subject comprising a MAP3K15 genomic nucleicacid molecule or mRNA molecule, and if mRNA, optionally reversetranscribing the mRNA into cDNA. Such assays can comprise, for exampledetermining the identity of these positions of the particular MAP3K15nucleic acid molecule. In some embodiments, the method is an in vitromethod.

In some embodiments, the determining step, detecting step, or sequenceanalysis comprises sequencing at least a portion of the nucleotidesequence of the MAP3K15 genomic nucleic acid molecule, the MAP3K15 mRNAmolecule, or the MAP3K15 cDNA molecule in the biological sample, whereinthe sequenced portion comprises one or more variations that cause aloss-of-function (partial or complete) or are predicted to cause aloss-of-function (partial or complete).

In some embodiments, the assay comprises sequencing the entire nucleicacid molecule. In some embodiments, only a MAP3K15 genomic nucleic acidmolecule is analyzed. In some embodiments, only a MAP3K15 mRNA isanalyzed. In some embodiments, only a MAP3K15 cDNA obtained from MAP3K15mRNA is analyzed.

Alteration-specific polymerase chain reaction techniques can be used todetect mutations such as SNPs in a nucleic acid sequence.Alteration-specific primers can be used because the DNA polymerase willnot extend when a mismatch with the template is present.

In some embodiments, the nucleic acid molecule in the sample is mRNA andthe mRNA is reverse-transcribed into a cDNA prior to the amplifyingstep. In some embodiments, the nucleic acid molecule is present within acell obtained from the subject.

In some embodiments, the assay comprises contacting the biologicalsample with a primer or probe, such as an alteration-specific primer oralteration-specific probe, that specifically hybridizes to a MAP3K15variant genomic sequence, variant mRNA sequence, or variant cDNAsequence and not the corresponding MAP3K15 reference sequence understringent conditions, and determining whether hybridization hasoccurred.

In some embodiments, the determining step, detecting step, or sequenceanalysis comprises: a) amplifying at least a portion of the nucleic acidmolecule that encodes the MAP3K15 polypeptide; b) labeling the amplifiednucleic acid molecule with a detectable label; c) contacting the labelednucleic acid molecule with a support comprising an alteration-specificprobe; and d) detecting the detectable label.

In some embodiments, the assay comprises RNA sequencing (RNA-Seq). Insome embodiments, the assays also comprise reverse transcribing mRNAinto cDNA, such as by the reverse transcriptase polymerase chainreaction (RT-PCR).

In some embodiments, the methods utilize probes and primers ofsufficient nucleotide length to bind to the target nucleotide sequenceand specifically detect and/or identify a polynucleotide comprising aMAP3K15 variant genomic nucleic acid molecule, variant mRNA molecule, orvariant cDNA molecule. The hybridization conditions or reactionconditions can be determined by the operator to achieve this result. Thenucleotide length may be any length that is sufficient for use in adetection method of choice, including any assay described or exemplifiedherein. Such probes and primers can hybridize specifically to a targetnucleotide sequence under high stringency hybridization conditions.Probes and primers may have complete nucleotide sequence identity ofcontiguous nucleotides within the target nucleotide sequence, althoughprobes differing from the target nucleotide sequence and that retain theability to specifically detect and/or identify a target nucleotidesequence may be designed by conventional methods. Probes and primers canhave about 80%, about 85%, about 90%, about 91%, about 92%, about 93%,about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or100% sequence identity or complementarity with the nucleotide sequenceof the target nucleic acid molecule.

Illustrative examples of nucleic acid sequencing techniques include, butare not limited to, chain terminator (Sanger) sequencing and dyeterminator sequencing. Other methods involve nucleic acid hybridizationmethods other than sequencing, including using labeled primers or probesdirected against purified DNA, amplified DNA, and fixed cellpreparations (fluorescence in situ hybridization (FISH)). In somemethods, a target nucleic acid molecule may be amplified prior to orsimultaneous with detection. Illustrative examples of nucleic acidamplification techniques include, but are not limited to, polymerasechain reaction (PCR), ligase chain reaction (LCR), strand displacementamplification (SDA), and nucleic acid sequence based amplification(NASBA). Other methods include, but are not limited to, ligase chainreaction, strand displacement amplification, and thermophilic SDA(tSDA).

In hybridization techniques, stringent conditions can be employed suchthat a probe or primer will specifically hybridize to its target. Insome embodiments, a polynucleotide primer or probe under stringentconditions will hybridize to its target sequence to a detectably greaterdegree than to other non-target sequences, such as, at least 2-fold, atleast 3-fold, at least 4-fold, or more over background, including over10-fold over background. In some embodiments, a polynucleotide primer orprobe under stringent conditions will hybridize to its target nucleotidesequence to a detectably greater degree than to other nucleotidesequences by at least 2-fold. In some embodiments, a polynucleotideprimer or probe under stringent conditions will hybridize to its targetnucleotide sequence to a detectably greater degree than to othernucleotide sequences by at least 3-fold. In some embodiments, apolynucleotide primer or probe under stringent conditions will hybridizeto its target nucleotide sequence to a detectably greater degree than toother nucleotide sequences by at least 4-fold. In some embodiments, apolynucleotide primer or probe under stringent conditions will hybridizeto its target nucleotide sequence to a detectably greater degree than toother nucleotide sequences by over 10-fold over background. Stringentconditions are sequence-dependent and will be different in differentcircumstances.

Appropriate stringency conditions which promote DNA hybridization, forexample, 6× sodium chloride/sodium citrate (SSC) at about 45° C.,followed by a wash of 2×SSC at 50° C., are known or can be found inCurrent Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989),6.3.1-6.3.6. Typically, stringent conditions for hybridization anddetection will be those in which the salt concentration is less thanabout 1.5 M Na⁺ ion, typically about 0.01 to 1.0 M Na⁺ ion concentration(or other salts) at pH 7.0 to 8.3 and the temperature is at least about30° C. for short probes (such as, for example, 10 to 50 nucleotides) andat least about 60° C. for longer probes (such as, for example, greaterthan 50 nucleotides). Stringent conditions may also be achieved with theaddition of destabilizing agents such as formamide. Optionally, washbuffers may comprise about 0.1% to about 1% SDS. Duration ofhybridization is generally less than about 24 hours, usually about 4 toabout 12 hours. The duration of the wash time will be at least a lengthof time sufficient to reach equilibrium.

In some embodiments, such isolated nucleic acid molecules comprise orconsist of at least about 5, at least about 8, at least about 10, atleast about 11, at least about 12, at least about 13, at least about 14,at least about 15, at least about 16, at least about 17, at least about18, at least about 19, at least about 20, at least about 21, at leastabout 22, at least about 23, at least about 24, at least about 25, atleast about 30, at least about 35, at least about 40, at least about 45,at least about 50, at least about 55, at least about 60, at least about65, at least about 70, at least about 75, at least about 80, at leastabout 85, at least about 90, at least about 95, at least about 100, atleast about 200, at least about 300, at least about 400, at least about500, at least about 600, at least about 700, at least about 800, atleast about 900, at least about 1000, at least about 2000, at leastabout 3000, at least about 4000, or at least about 5000 nucleotides. Insome embodiments, such isolated nucleic acid molecules comprise orconsist of at least about 5, at least about 8, at least about 10, atleast about 11, at least about 12, at least about 13, at least about 14,at least about 15, at least about 16, at least about 17, at least about18, at least about 19, at least about 20, at least about 21, at leastabout 22, at least about 23, at least about 24, or at least about 25nucleotides. In some embodiments, the isolated nucleic acid moleculescomprise or consist of at least about 18 nucleotides. In someembodiments, the isolated nucleic acid molecules comprise or consists ofat least about 15 nucleotides. In some embodiments, the isolated nucleicacid molecules consist of or comprise from about 10 to about 35, fromabout 10 to about 30, from about 10 to about 25, from about 12 to about30, from about 12 to about 28, from about 12 to about 24, from about 15to about 30, from about 15 to about 25, from about 18 to about 30, fromabout 18 to about 25, from about 18 to about 24, or from about 18 toabout 22 nucleotides. In some embodiments, the isolated nucleic acidmolecules consist of or comprise from about 18 to about 30 nucleotides.In some embodiments, the isolated nucleic acid molecules comprise orconsist of at least about 15 nucleotides to at least about 35nucleotides.

In some embodiments, such isolated nucleic acid molecules hybridize toMAP3K15 missense variant nucleic acid molecules (such as genomic nucleicacid molecules, mRNA molecules, and/or cDNA molecules) under stringentconditions. Such nucleic acid molecules can be used, for example, asprobes, primers, alteration-specific probes, or alteration-specificprimers as described or exemplified herein, and include, withoutlimitation primers, probes, antisense RNAs, shRNAs, and siRNAs, each ofwhich is described in more detail elsewhere herein, and can be used inany of the methods described herein.

In some embodiments, the isolated nucleic acid molecules hybridize to atleast about 15 contiguous nucleotides of a nucleic acid molecule that isat least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, at least about 96%,at least about 97%, at least about 98%, at least about 99%, or 100%identical to a MAP3K15 missense variant genomic nucleic acid molecule, aMAP3K15 missense variant mRNA molecule, and/or a MAP3K15 missensevariant cDNA molecule. In some embodiments, the isolated nucleic acidmolecules consist of or comprise from about 15 to about 100 nucleotides,or from about 15 to about 35 nucleotides. In some embodiments, theisolated nucleic acid molecules consist of or comprise from about 15 toabout 100 nucleotides. In some embodiments, the isolated nucleic acidmolecules consist of or comprise from about 15 to about 35 nucleotides.

In some embodiments, the alteration-specific probes andalteration-specific primers comprise DNA. In some embodiments, thealteration-specific probes and alteration-specific primers comprise RNA.

In some embodiments, the probes and primers described herein (includingalteration-specific probes and alteration-specific primers) have anucleotide sequence that specifically hybridizes to any of the nucleicacid molecules disclosed herein, or the complement thereof. In someembodiments, the probes and primers specifically hybridize to any of thenucleic acid molecules disclosed herein under stringent conditions.

In some embodiments, the primers, including alteration-specific primers,can be used in second generation sequencing or high throughputsequencing. In some instances, the primers, includingalteration-specific primers, can be modified. In particular, the primerscan comprise various modifications that are used at different steps of,for example, Massive Parallel Signature Sequencing (MPSS), Polonysequencing, and 454 Pyrosequencing. Modified primers can be used atseveral steps of the process, including biotinylated primers in thecloning step and fluorescently labeled primers used at the bead loadingstep and detection step. Polony sequencing is generally performed usinga paired-end tags library wherein each molecule of DNA template is about135 bp in length. Biotinylated primers are used at the bead loading stepand emulsion PCR. Fluorescently labeled degenerate nonameroligonucleotides are used at the detection step. An adaptor can containa 5′-biotin tag for immobilization of the DNA library ontostreptavidin-coated beads.

The probes and primers described herein can be used to detect anucleotide variation within any of the MAP3K15 variant missense genomicnucleic acid molecules, MAP3K15 missense variant mRNA molecules, and/orMAP3K15 missense variant cDNA molecules disclosed herein. The primersdescribed herein can be used to amplify MAP3K15 missense variant genomicnucleic acid molecules, MAP3K15 missense variant mRNA molecules, orMAP3K15 missense variant cDNA molecules, or a fragment thereof.

In the context of the disclosure “specifically hybridizes” means thatthe probe or primer (such as, for example, the alteration-specific probeor alteration-specific primer) does not hybridize to a nucleic acidsequence encoding a MAP3K15 reference genomic nucleic acid molecule, aMAP3K15 reference mRNA molecule, and/or a MAP3K15 reference cDNAmolecule.

In some embodiments, the probes (such as, for example, analteration-specific probe) comprise a label. In some embodiments, thelabel is a fluorescent label, a radiolabel, or biotin.

The present disclosure also provides supports comprising a substrate towhich any one or more of the probes disclosed herein is attached. Solidsupports are solid-state substrates or supports with which molecules,such as any of the probes disclosed herein, can be associated. A form ofsolid support is an array. Another form of solid support is an arraydetector. An array detector is a solid support to which multipledifferent probes have been coupled in an array, grid, or other organizedpattern. A form for a solid-state substrate is a microtiter dish, suchas a standard 96-well type. In some embodiments, a multiwell glass slidecan be employed that normally contains one array per well.

The nucleotide sequence of a MAP3K15 reference genomic nucleic acidmolecule is set forth in SEQ ID NO:1.

The nucleotide sequence of a MAP3K15 reference mRNA molecule is setforth in SEQ ID NO:2. The nucleotide sequence of another MAP3K15reference mRNA molecule is set forth in SEQ ID NO:3. The nucleotidesequence of another MAP3K15 reference mRNA molecule is set forth in SEQID NO:4. The nucleotide sequence of another MAP3K15 reference mRNAmolecule is set forth in SEQ ID NO:5. The nucleotide sequence of anotherMAP3K15 reference mRNA molecule is set forth in SEQ ID NO:6. Thenucleotide sequence of another MAP3K15 reference mRNA molecule is setforth in SEQ ID NO:7.

The nucleotide sequence of a MAP3K15 reference cDNA molecule is setforth in SEQ ID NO:8. The nucleotide sequence of another MAP3K15reference cDNA molecule is set forth in SEQ ID NO:9. The nucleotidesequence of another MAP3K15 reference cDNA molecule is set forth in SEQID NO:10. The nucleotide sequence of another MAP3K15 reference cDNAmolecule is set forth in SEQ ID NO:11. The nucleotide sequence ofanother MAP3K15 reference cDNA molecule is set forth in SEQ ID NO:12.The nucleotide sequence of another MAP3K15 reference cDNA molecule isset forth in SEQ ID NO:13.

The amino acid sequence of a MAP3K15 reference polypeptide is set forthin SEQ ID NO:14, and is 1,313 amino acids in length. The amino acidsequence of another MAP3K15 reference polypeptide is set forth in SEQ IDNO:15, and is 788 amino acids in length. The amino acid sequence ofanother MAP3K15 reference polypeptide is set forth in SEQ ID NO:16, andis 748 amino acids in length. The amino acid sequence of another MAP3K15reference polypeptide is set forth in SEQ ID NO:17, and is 247 aminoacids in length. The amino acid sequence of another MAP3K15 referencepolypeptide is set forth in SEQ ID NO:18, and is 1,145 amino acids inlength.

The genomic nucleic acid molecules, mRNA molecules, and cDNA moleculescan be from any organism. For example, the genomic nucleic acidmolecules, mRNA molecules, and cDNA molecules can be human or anortholog from another organism, such as a non-human mammal, a rodent, amouse, or a rat. It is understood that gene sequences within apopulation can vary due to polymorphisms such as single-nucleotidepolymorphisms. The examples provided herein are only exemplarysequences. Other sequences are also possible.

Also provided herein are functional polynucleotides that can interactwith the disclosed nucleic acid molecules. Examples of functionalpolynucleotides include, but are not limited to, antisense molecules,aptamers, ribozymes, triplex forming molecules, and external guidesequences. The functional polynucleotides can act as effectors,inhibitors, modulators, and stimulators of a specific activity possessedby a target molecule, or the functional polynucleotides can possess a denovo activity independent of any other molecules.

The isolated nucleic acid molecules disclosed herein can comprise RNA,DNA, or both RNA and DNA. The isolated nucleic acid molecules can alsobe linked or fused to a heterologous nucleic acid sequence, such as in avector, or a heterologous label. For example, the isolated nucleic acidmolecules disclosed herein can be within a vector or as an exogenousdonor sequence comprising the isolated nucleic acid molecule and aheterologous nucleic acid sequence. The isolated nucleic acid moleculescan also be linked or fused to a heterologous label. The label can bedirectly detectable (such as, for example, fluorophore) or indirectlydetectable (such as, for example, hapten, enzyme, or fluorophorequencher). Such labels can be detectable by spectroscopic,photochemical, biochemical, immunochemical, or chemical means. Suchlabels include, for example, radiolabels, pigments, dyes, chromogens,spin labels, and fluorescent labels. The label can also be, for example,a chemiluminescent substance; a metal-containing substance; or anenzyme, where there occurs an enzyme-dependent secondary generation ofsignal. The term “label” can also refer to a “tag” or hapten that canbind selectively to a conjugated molecule such that the conjugatedmolecule, when added subsequently along with a substrate, is used togenerate a detectable signal. For example, biotin can be used as a tagalong with an avidin or streptavidin conjugate of horseradish peroxidate(HRP) to bind to the tag, and examined using a calorimetric substrate(such as, for example, tetramethylbenzidine (TMB)) or a fluorogenicsubstrate to detect the presence of HRP. Exemplary labels that can beused as tags to facilitate purification include, but are not limited to,myc, HA, FLAG or 3×FLAG, 6×His or polyhistidine,glutathione-S-transferase (GST), maltose binding protein, an epitopetag, or the Fc portion of immunoglobulin. Numerous labels include, forexample, particles, fluorophores, haptens, enzymes and theircalorimetric, fluorogenic and chemiluminescent substrates and otherlabels.

The isolated nucleic acid molecules, or the complement thereof, can alsobe present within a host cell. In some embodiments, the host cell cancomprise the vector that comprises any of the nucleic acid moleculesdescribed herein, or the complement thereof. In some embodiments, thenucleic acid molecule is operably linked to a promoter active in thehost cell. In some embodiments, the promoter is an exogenous promoter.In some embodiments, the promoter is an inducible promoter. In someembodiments, the host cell is a bacterial cell, a yeast cell, an insectcell, or a mammalian cell. In some embodiments, the host cell is abacterial cell. In some embodiments, the host cell is a yeast cell. Insome embodiments, the host cell is an insect cell. In some embodiments,the host cell is a mammalian cell.

The disclosed nucleic acid molecules can comprise, for example,nucleotides or non-natural or modified nucleotides, such as nucleotideanalogs or nucleotide substitutes. Such nucleotides include a nucleotidethat contains a modified base, sugar, or phosphate group, or thatincorporates a non-natural moiety in its structure. Examples ofnon-natural nucleotides include, but are not limited to,dideoxynucleotides, biotinylated, aminated, deaminated, alkylated,benzylated, and fluorophor-labeled nucleotides.

The nucleic acid molecules disclosed herein can also comprise one ormore nucleotide analogs or substitutions. A nucleotide analog is anucleotide which contains a modification to either the base, sugar, orphosphate moieties. Modifications to the base moiety include, but arenot limited to, natural and synthetic modifications of A, C, G, and T/U,as well as different purine or pyrimidine bases such as, for example,pseudouridine, uracil-5-yl, hypoxanthin-9-yl (I), and2-aminoadenin-9-yl. Modified bases include, but are not limited to,5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine,hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives ofadenine and guanine, 2-propyl and other alkyl derivatives of adenine andguanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouraciland cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine andthymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino,8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines andguanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl andother 5-substituted uracils and cytosines, 7-methylguanine,7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine,7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

Nucleotide analogs can also include modifications of the sugar moiety.Modifications to the sugar moiety include, but are not limited to,natural modifications of the ribose and deoxy ribose as well assynthetic modifications. Sugar modifications include, but are notlimited to, the following modifications at the 2′ position: OH; F; O-,S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; orO-alkyl-O-alkyl, wherein the alkyl, alkenyl, and alkynyl may besubstituted or unsubstituted C₁₋₁₀alkyl or C₂₋₁₀alkenyl, andC₂₋₁₀alkynyl. Exemplary 2′ sugar modifications also include, but are notlimited to, —O[(CH₂)_(n)O]_(m)CH₃, —O(CH₂)_(n)OCH₃, —O(CH₂)_(n)NH₂,—O(CH₂)_(n)CH₃, —O(CH₂)_(n)—ONH₂, and —O(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂,where n and m, independently, are from 1 to about 10. Othermodifications at the 2′ position include, but are not limited to,C₁₋₁₀alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl orO-aralkyl, SH, SCH₃, OCN, CI, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂,NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,polyalkylamino, substituted silyl, an RNA cleaving group, a reportergroup, an intercalator, a group for improving the pharmacokineticproperties of an oligonucleotide, or a group for improving thepharmacodynamic properties of an oligonucleotide, and other substituentshaving similar properties. Similar modifications may also be made atother positions on the sugar, particularly the 3′ position of the sugaron the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides andthe 5′ position of 5′ terminal nucleotide. Modified sugars can alsoinclude those that contain modifications at the bridging ring oxygen,such as CH₂ and S. Nucleotide sugar analogs can also have sugarmimetics, such as cyclobutyl moieties in place of the pentofuranosylsugar.

Nucleotide analogs can also be modified at the phosphate moiety.Modified phosphate moieties include, but are not limited to, those thatcan be modified so that the linkage between two nucleotides contains aphosphorothioate, chiral phosphorothioate, phosphorodithioate,phosphotriester, aminoalkylphosphotriester, methyl and other alkylphosphonates including 3′-alkylene phosphonate and chiral phosphonates,phosphinates, phosphoramidates including 3′-amino phosphoramidate andaminoalkylphosphoramidates, thionophosphoramidates,thionoalkylphosphonates, thionoalkylphosphotriesters, andboranophosphates. These phosphate or modified phosphate linkage betweentwo nucleotides can be through a 3′-5′ linkage or a 2′-5′ linkage, andthe linkage can contain inverted polarity such as 3′-5′ to 5′-3′ or2′-5′ to 5′-2′. Various salts, mixed salts, and free acid forms are alsoincluded. Nucleotide substitutes also include peptide nucleic acids(PNAs).

The present disclosure also provides vectors comprising any one or moreof the nucleic acid molecules disclosed herein. In some embodiments, thevectors comprise any one or more of the nucleic acid molecules disclosedherein and a heterologous nucleic acid. The vectors can be viral ornonviral vectors capable of transporting a nucleic acid molecule. Insome embodiments, the vector is a plasmid or cosmid (such as, forexample, a circular double-stranded DNA into which additional DNAsegments can be ligated). In some embodiments, the vector is a viralvector, wherein additional DNA segments can be ligated into the viralgenome. Expression vectors include, but are not limited to, plasmids,cosmids, retroviruses, adenoviruses, adeno-associated viruses (AAV),plant viruses such as cauliflower mosaic virus and tobacco mosaic virus,yeast artificial chromosomes (YACs), Epstein-Barr (EBV)-derivedepisomes, and other expression vectors known in the art.

Desired regulatory sequences for mammalian host cell expression caninclude, for example, viral elements that direct high levels ofpolypeptide expression in mammalian cells, such as promoters and/orenhancers derived from retroviral LTRs, cytomegalovirus (CMV) (such as,for example, CMV promoter/enhancer), Simian Virus 40 (SV40) (such as,for example, SV40 promoter/enhancer), adenovirus, (such as, for example,the adenovirus major late promoter (AdMLP)), polyoma and strongmammalian promoters such as native immunoglobulin and actin promoters.Methods of expressing polypeptides in bacterial cells or fungal cells(such as, for example, yeast cells) are also well known. A promoter canbe, for example, a constitutively active promoter, a conditionalpromoter, an inducible promoter, a temporally restricted promoter (suchas, for example, a developmentally regulated promoter), or a spatiallyrestricted promoter (such as, for example, a cell-specific ortissue-specific promoter).

Percent identity (or percent complementarity) between particularstretches of nucleotide sequences within nucleic acid molecules or aminoacid sequences within polypeptides can be determined routinely usingBLAST programs (basic local alignment search tools) and PowerBLASTprograms (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang andMadden, Genome Res., 1997, 7, 649-656) or by using the Gap program(Wisconsin Sequence Analysis Package, Version 8 for Unix, GeneticsComputer Group, University Research Park, Madison Wis.), using defaultsettings, which uses the algorithm of Smith and Waterman (Adv. Appl.Math., 1981, 2, 482-489). Herein, if reference is made to percentsequence identity, the higher percentages of sequence identity arepreferred over the lower ones.

As used herein, the phrase “corresponding to” or grammatical variationsthereof when used in the context of the numbering of a particularnucleotide or nucleotide sequence or position refers to the numbering ofa specified reference sequence when the particular nucleotide ornucleotide sequence is compared to a reference sequence (such as, forexample, SEQ ID NO:1). In other words, the residue (such as, forexample, nucleotide or amino acid) number or residue (such as, forexample, nucleotide or amino acid) position of a particular polymer isdesignated with respect to the reference sequence rather than by theactual numerical position of the residue within the particularnucleotide or nucleotide sequence. For example, a particular nucleotidesequence can be aligned to a reference sequence by introducing gaps tooptimize residue matches between the two sequences. In these cases,although the gaps are present, the numbering of the residue in theparticular nucleotide or nucleotide sequence is made with respect to thereference sequence to which it has been aligned.

The nucleotide and amino acid sequences listed in the accompanyingsequence listing are shown using standard letter abbreviations fornucleotide bases, and three-letter code for amino acids. The nucleotidesequences follow the standard convention of beginning at the 5′ end ofthe sequence and proceeding forward (i.e., from left to right in eachline) to the 3′ end. Only one strand of each nucleotide sequence isshown, but the complementary strand is understood to be included by anyreference to the displayed strand. The amino acid sequence follows thestandard convention of beginning at the amino terminus of the sequenceand proceeding forward (i.e., from left to right in each line) to thecarboxy terminus.

The present disclosure also provides therapeutic agents that treat orprevent a metabolic disorder for use in the treatment and/or preventionof a metabolic disorder in a subject having: a MAP3K15 missense variantgenomic nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide; a MAP3K15 missense variant mRNA moleculeencoding a MAP3K15 predicted loss-of-function polypeptide; or a MAP3K15missense variant cDNA molecule encoding a MAP3K15 predictedloss-of-function polypeptide. Any of the therapeutic agents that treator prevent a metabolic disorder described herein can be used in thesemethods. The metabolic disorder can be Type-2 diabetes, increasedhemoglobin A1c, or increased serum glucose.

The present disclosure also provides uses of therapeutic agents thattreat or prevent a metabolic disorder for use in the preparation of amedicament for treating and/or preventing the metabolic disorder in asubject having: a MAP3K15 missense variant genomic nucleic acid moleculeencoding a MAP3K15 predicted loss-of-function polypeptide; a MAP3K15missense variant mRNA molecule encoding a MAP3K15 predictedloss-of-function polypeptide; or a MAP3K15 missense variant cDNAmolecule encoding a MAP3K15 predicted loss-of-function polypeptide. Anyof the therapeutic agents that treat or prevent a metabolic disorderdescribed herein can be used in these methods. The metabolic disordercan be Type-2 diabetes, increased hemoglobin A1c, or increased serumglucose.

The present disclosure also provides MAP3K15 inhibitors for use in thetreatment and/or prevention of a metabolic disorder in a subject that:a) is reference for a MAP3K15 genomic nucleic acid molecule, a MAP3K15mRNA molecule, or a MAP3K15 cDNA molecule; or b) is heterozygous for: i)a MAP3K15 missense variant genomic nucleic acid molecule encoding aMAP3K15 predicted loss-of-function polypeptide; ii) a MAP3K15 missensevariant mRNA molecule encoding a MAP3K15 predicted loss-of-functionpolypeptide; or iii) a MAP3K15 missense variant cDNA molecule encoding aMAP3K15 predicted loss-of-function polypeptide. Any of the MAP3K15inhibitors described herein can be used in these methods. The metabolicdisorder can be Type-2 diabetes, increased hemoglobin A1c, or increasedserum glucose.

The present disclosure also provides uses of MAP3K15 inhibitors in thepreparation of a medicament for treating and/or preventing a metabolicdisorder in a subject that: a) is reference for a MAP3K15 genomicnucleic acid molecule, a MAP3K15 mRNA molecule, or a MAP3K15 cDNAmolecule; or b) is heterozygous for: i) a MAP3K15 missense variantgenomic nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide; ii) a MAP3K15 missense variant mRNAmolecule encoding a MAP3K15 predicted loss-of-function polypeptide; oriii) a MAP3K15 missense variant cDNA molecule encoding a MAP3K15predicted loss-of-function polypeptide. Any of the MAP3K15 inhibitorsdescribed herein can be used in these methods. The metabolic disordercan be Type-2 diabetes, increased hemoglobin A1c, or increased serumglucose.

All patent documents, websites, other publications, accession numbersand the like cited above or below are incorporated by reference in theirentirety for all purposes to the same extent as if each individual itemwere specifically and individually indicated to be so incorporated byreference. If different versions of a sequence are associated with anaccession number at different times, the version associated with theaccession number at the effective filing date of this application ismeant. The effective filing date means the earlier of the actual filingdate or filing date of a priority application referring to the accessionnumber if applicable. Likewise, if different versions of a publication,website or the like are published at different times, the version mostrecently published at the effective filing date of the application ismeant unless otherwise indicated. Any feature, step, element,embodiment, or aspect of the present disclosure can be used incombination with any other feature, step, element, embodiment, or aspectunless specifically indicated otherwise. Although the present disclosurehas been described in some detail by way of illustration and example forpurposes of clarity and understanding, it will be apparent that certainchanges and modifications may be practiced within the scope of theappended claims.

The following examples are provided to describe the embodiments ingreater detail. They are intended to illustrate, not to limit, theclaimed embodiments. The following examples provide those of ordinaryskill in the art with a disclosure and description of how the compounds,compositions, articles, devices and/or methods described herein are madeand evaluated, and are intended to be purely exemplary and are notintended to limit the scope of any claims. Efforts have been made toensure accuracy with respect to numbers (such as, for example, amounts,temperature, etc.), but some errors and deviations may be accounted for.Unless indicated otherwise, parts are parts by weight, temperature is in° C. or is at ambient temperature, and pressure is at or nearatmospheric.

EXAMPLES Example 1: Novel Association Between MAP3K15 and Protectionfrom Type-2 Diabetes

The exomes of 454,787 UKB study participants were sequenced, with 95.8%of targeted bases covered at a depth of 20× or greater, as previouslydescribed (Szustakowski, Advancing Human Genetics Research and DrugDiscovery through Exome Sequencing of the UK Biobank. bioRxiv, 2021; andVan Hout et al., Nature, 2020). Twelve million variants were identifiedin 39 million base pairs across the coding regions of 18,659 genes (datanot shown). Among the variants identified were 3,375,252 (median of10,260 per individual) synonymous, 7,689,495 (9,284 per individual)missense and 889,957 (212 per individual) putative loss-of-function(pLOF) variants (data not shown), of which about half were observed onlyonce in this dataset (singleton variants; data not shown).

A novel association was discovered between a burden of predictedloss-of-function (pLOF) and deleterious missense variants in MAP3K15 andboth lower levels of hemoglobin A1c (7,551 carriers; effect=−0.09 SD,95% CI −0.10 to −0.073, P=2×10⁻³¹) and lower serum glucose (6,885carriers; effect=−0.090, 95% CI −0.110 to −0.073, P=1.7×10⁻²⁵). Inaddition, a burden of pLOFs and deleterious missense variants in MAP3K15was also associated with protection from Type-2 diabetes (7,863carriers; OR=0.80, 95% CI 0.74 to 0.87, P=1×10⁻²). Furthermore, therewas supporting evidence in a GHS study (a health system-based cohortfrom central and eastern Pennsylvania (USA) with ongoing recruitmentsince 2006) for all three phenotypes: hemoglobin A1c (1,304 carriers;effect=−0.040 SD units, 95% CI −0.079 to −0.002, P=0.038), glucose(1,754 carriers; effect=−0.097 SD units, 95% CI −0.130 to −0.064,P=1.3×10⁻⁸) and type-2 diabetes (2,455 carriers; OR=0.91, 95% CI 0.84 to0.98, P=0.018).

Various modifications of the described subject matter, in addition tothose described herein, will be apparent to those skilled in the artfrom the foregoing description. Such modifications are also intended tofall within the scope of the appended claims. Each reference (including,but not limited to, journal articles, U.S. and non-U.S. patents, patentapplication publications, international patent application publications,gene bank accession numbers, and the like) cited in the presentapplication is incorporated herein by reference in its entirety and forall purposes.

1. A method of treating a subject having a metabolic disorder or at riskof developing a metabolic disorder, the method comprising administeringa Mitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) inhibitorto the subject.
 2. The method according to claim 1, wherein themetabolic disorder is Type-2 diabetes, increased hemoglobin A1c, orincreased serum glucose. 3-4. (canceled)
 5. The method according toclaim 1, wherein the MAP3K15 inhibitor comprises an inhibitory nucleicacid molecule that hybridizes to a MAP3K15 nucleic acid molecule.
 6. Themethod according to claim 5, wherein the inhibitory nucleic acidmolecule comprises an antisense nucleic acid molecule, a smallinterfering RNA (siRNA), or a short hairpin RNA (shRNA). 7-12.(canceled)
 13. The method according to claim 1, further comprisingdetecting the presence or absence of a MAP3K15 missense variant nucleicacid molecule encoding a MAP3K15 predicted loss-of-function polypeptidein a biological sample from the subject.
 14. The method according toclaim 13, further comprising administering a therapeutic agent thattreats or prevents the metabolic disorder in a standard dosage amount toa subject wherein the MAP3K15 missense variant nucleic acid molecule isabsent from the biological sample.
 15. The method according to claim 13,further comprising administering a therapeutic agent that treats orprevents the metabolic disorder in a dosage amount that is the same asor less than a standard dosage amount to a subject that is heterozygousfor the MAP3K15 missense variant nucleic acid molecule.
 16. The methodaccording to claim 13, wherein the MAP3K15 predicted missense variantnucleic acid molecule is a splice-site variant, a stop-gain variant, astart-loss variant, a stop-loss variant, a frameshift variant, or anin-frame indel variant, or a variant that encodes a truncated MAP3K15predicted loss-of-function polypeptide.
 17. The method according toclaim 16, wherein the MAP3K15 missense variant nucleic acid moleculeencodes a truncated MAP3K15 predicted loss-of-function polypeptide. 18.A method of treating a subject with a therapeutic agent that treats orprevents a metabolic disorder, wherein the subject has a metabolicdisorder or is at risk of developing a metabolic disorder, the methodcomprising the steps of: determining whether the subject has aMitogen-Activated Protein Kinase Kinase Kinase 15 (MAP3K15) missensevariant nucleic acid molecule encoding a MAP3K15 predictedloss-of-function polypeptide by: obtaining or having obtained abiological sample from the subject; and performing or having performed asequence analysis on the biological sample to determine if the subjecthas a genotype comprising the MAP3K15 missense variant nucleic acidmolecule; and administering or continuing to administer the therapeuticagent that treats or prevents the metabolic disorder in a standarddosage amount to a subject that is MAP3K15 reference, and/oradministering a MAP3K15 inhibitor to the subject; administering orcontinuing to administer the therapeutic agent that treats or preventsthe metabolic disorder in an amount that is the same as or less than astandard dosage amount to a subject that is heterozygous for the MAP3K15missense variant nucleic acid molecule, and/or administering a MAP3K15inhibitor to the subject; or administering or continuing to administerthe therapeutic agent that treats or prevents the metabolic disorder inan amount that is the same as or less than a standard dosage amount to asubject that is homozygous for the MAP3K15 missense variant nucleic acidmolecule; wherein the presence of a genotype having the MAP3K15 missensevariant nucleic acid molecule encoding the MAP3K15 predictedloss-of-function polypeptide indicates the subject has a decreased riskof developing the metabolic disorder.
 19. The method according to claim18, wherein the subject is MAP3K15 reference, and the subject isadministered or continued to be administered the therapeutic agent thattreats or prevents the metabolic disorder in a standard dosage amount,and is administered a MAP3K15 inhibitor.
 20. The method according toclaim 18, wherein the subject is heterozygous for a MAP3K15 missensevariant nucleic acid molecule, and the subject is administered orcontinued to be administered the therapeutic agent that treats orprevents the metabolic disorder in an amount that is the same as or lessthan a standard dosage amount, and is administered a MAP3K15 inhibitor.21. The method according to claim 18, wherein the MAP3K15 missensevariant nucleic acid molecule is a splice-site variant, a stop-gainvariant, a start-loss variant, a stop-loss variant, a frameshiftvariant, or an in-frame indel variant, or a variant that encodes atruncated MAP3K15 predicted loss-of-function polypeptide.
 22. The methodaccording to claim 18, wherein the MAP3K15 missense variant nucleic acidmolecule encodes a truncated MAP3K15 predicted loss-of-functionpolypeptide.
 23. The method according to claim 18, wherein the MAP3K15inhibitor comprises an inhibitory nucleic acid molecule that hybridizesto a MAP3K15 nucleic acid molecule.
 24. The method according to claim23, wherein the inhibitory nucleic acid molecule comprises an antisensenucleic acid molecule, a small interfering RNA (siRNA), or a shorthairpin RNA (shRNA). 25-30. (canceled)
 31. The method according to claim18, wherein the metabolic disorder is Type-2 diabetes.
 32. The methodaccording to claim 18, wherein the metabolic disorder is increasedhemoglobin A1c.
 33. The method according to claim 18, wherein themetabolic disorder is increased serum glucose.
 34. The method accordingto claim 18, wherein the metabolic disorder is Type-2 diabetes, and thetherapeutic agent is chosen from metformin, an insulin, a sulfonylurea,a meglitinide, a thiazolidinedione, a DPP-4 inhibitor, a GLP-1 receptoragonist, and an SGLT2 inhibitor, or any combination thereof.
 35. Themethod according to claim 18, wherein the metabolic disorder is Type-2diabetes, and therapeutic agent is chosen from metformin, insulin,glyburide, glipizide, glimepiride, repaglinide, nateglinide,rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin,exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, andempagliflozin, or any combination thereof. 36-73. (canceled)